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Showing 1 - 200 of 3120 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 8)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 26, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 90, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 379, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 26, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 237, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 25, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 5)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 7)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 139, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 27, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 4)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 9, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 23, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 6, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 26, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 7)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 6)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Ecological Research     Full-text available via subscription   (Followers: 47, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 27, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 46, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 52, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 17, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 27)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 10)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 9, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 7)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 370, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 9, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 31, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 45, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 338, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 9, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 432, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 56, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 9, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 49, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 48, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 48, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 42, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 9, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 45, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 208, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 61, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 24, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 26, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 36, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 60, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 14)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 36, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 171, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 176, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)

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Journal Cover American Journal of Human Genetics
  [SJR: 8.769]   [H-I: 256]   [32 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3123 journals]
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 197 - 198
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.007
  • Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome
    • Authors: Laura Bozal-Basterra; Itziar Martín-Ruíz; Lucia Pirone; Yinwen Liang; Jón Otti Sigurðsson; Maria Gonzalez-Santamarta; Immacolata Giordano; Estibaliz Gabicagogeascoa; Angela de Luca; Jose A. Rodríguez; Andrew O.M. Wilkie; Jürgen Kohlhase; Deborah Eastwood; Christopher Yale; Jesper V. Olsen; Michael Rauchman; Kathryn V. Anderson; James D. Sutherland; Rosa Barrio
      Pages: 249 - 265
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Laura Bozal-Basterra, Itziar Martín-Ruíz, Lucia Pirone, Yinwen Liang, Jón Otti Sigurðsson, Maria Gonzalez-Santamarta, Immacolata Giordano, Estibaliz Gabicagogeascoa, Angela de Luca, Jose A. Rodríguez, Andrew O.M. Wilkie, Jürgen Kohlhase, Deborah Eastwood, Christopher Yale, Jesper V. Olsen, Michael Rauchman, Kathryn V. Anderson, James D. Sutherland, Rosa Barrio
      Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2017.12.017
  • Impaired Transferrin Receptor Palmitoylation and Recycling in
           Neurodegeneration with Brain Iron Accumulation
    • Authors: Anthony Drecourt; Joël Babdor; Michael Dussiot; Floriane Petit; Nicolas Goudin; Meriem Garfa-Traoré; Florence Habarou; Christine Bole-Feysot; Patrick Nitschké; Chris Ottolenghi; Metodi D. Metodiev; Valérie Serre; Isabelle Desguerre; Nathalie Boddaert; Olivier Hermine; Arnold Munnich; Agnès Rötig
      Pages: 266 - 277
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Anthony Drecourt, Joël Babdor, Michael Dussiot, Floriane Petit, Nicolas Goudin, Meriem Garfa-Traoré, Florence Habarou, Christine Bole-Feysot, Patrick Nitschké, Chris Ottolenghi, Metodi D. Metodiev, Valérie Serre, Isabelle Desguerre, Nathalie Boddaert, Olivier Hermine, Arnold Munnich, Agnès Rötig
      Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.003
  • OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3
           Microdeletion Syndrome
    • Authors: Mohammed Uddin; Brianna K. Unda; Vickie Kwan; Nicholas T. Holzapfel; Sean H. White; Leon Chalil; Marc Woodbury-Smith; Karen S. Ho; Erin Harward; Nadeem Murtaza; Biren Dave; Giovanna Pellecchia; Lia D’Abate; Thomas Nalpathamkalam; Sylvia Lamoureux; John Wei; Marsha Speevak; James Stavropoulos; Kristin J. Hope; Brad W. Doble; Jacob Nielsen; E. Robert Wassman; Stephen W. Scherer; Karun K. Singh
      Pages: 278 - 295
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Mohammed Uddin, Brianna K. Unda, Vickie Kwan, Nicholas T. Holzapfel, Sean H. White, Leon Chalil, Marc Woodbury-Smith, Karen S. Ho, Erin Harward, Nadeem Murtaza, Biren Dave, Giovanna Pellecchia, Lia D’Abate, Thomas Nalpathamkalam, Sylvia Lamoureux, John Wei, Marsha Speevak, James Stavropoulos, Kristin J. Hope, Brad W. Doble, Jacob Nielsen, E. Robert Wassman, Stephen W. Scherer, Karun K. Singh
      Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.006
  • Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3
           Microdeletion Syndrome
    • Authors: Jiani Yin; Wu Chen; Eugene S. Chao; Sirena Soriano; Li Wang; Wei Wang; Steven E. Cummock; Huifang Tao; Kaifang Pang; Zhandong Liu; Fred A. Pereira; Rodney C. Samaco; Huda Y. Zoghbi; Mingshan Xue; Christian P. Schaaf
      Pages: 296 - 308
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Jiani Yin, Wu Chen, Eugene S. Chao, Sirena Soriano, Li Wang, Wei Wang, Steven E. Cummock, Huifang Tao, Kaifang Pang, Zhandong Liu, Fred A. Pereira, Rodney C. Samaco, Huda Y. Zoghbi, Mingshan Xue, Christian P. Schaaf
      15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity.

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.005
  • Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone,
           Cause Early-Onset Epileptic Encephalopathy
    • Authors: Hiroki Mutoh; Mitsuhiro Kato; Tenpei Akita; Takuma Shibata; Hiroyuki Wakamoto; Hiroko Ikeda; Hiroki Kitaura; Kazushi Aoto; Mitsuko Nakashima; Tianying Wang; Chihiro Ohba; Satoko Miyatake; Noriko Miyake; Akiyoshi Kakita; Kensuke Miyake; Atsuo Fukuda; Naomichi Matsumoto; Hirotomo Saitsu
      Pages: 321 - 329
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Hiroki Mutoh, Mitsuhiro Kato, Tenpei Akita, Takuma Shibata, Hiroyuki Wakamoto, Hiroko Ikeda, Hiroki Kitaura, Kazushi Aoto, Mitsuko Nakashima, Tianying Wang, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Akiyoshi Kakita, Kensuke Miyake, Atsuo Fukuda, Naomichi Matsumoto, Hirotomo Saitsu
      Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20–35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.004
  • Bible Says Israelites Didn't Exterminate Sidonians
    • Authors: Paul Giem
      First page: 330
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Paul Giem

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.001
  • Response to Giem
    • Authors: Marc Haber; Claude Doumet-Serhal; Christiana Scheib; Yali Xue; Petr Danecek; Massimo Mezzavilla; Sonia Youhanna; Rui Martiniano; Javier Prado-Martinez; Michał Szpak; Elizabeth Matisoo-Smith; Holger Schutkowski; Richard Mikulski; Pierre Zalloua; Toomas Kivisild; Chris Tyler-Smith
      First page: 331
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Michał Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas Kivisild, Chris Tyler-Smith

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2018.01.002
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 1 - 2
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.11.010
  • Transitions in an Era of Disruptive Change
    • Authors: Bruce R. Korf
      Pages: 3 - 4
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Bruce R. Korf

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.011
  • HIPAA’s Individual Right of Access to Genomic Data: Reconciling
           Safety and Civil Rights
    • Authors: Barbara J. Evans
      Pages: 5 - 10
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Barbara J. Evans
      In 2014, the United States granted individuals a right of access to their own laboratory test results, including genomic data. Many observers feel that this right is in tension with regulatory and bioethical standards designed to protect the safety of people who undergo genomic testing. This commentary attributes this tension to growing pains within an expanding federal regulatory program for genetic and genomic testing. The Genetic Information Nondiscrimination Act of 2008 expanded the regulatory agenda to encompass civil rights and consumer safety. The individual access right, as it applies to genomic data, is best understood as a civil-rights regulation. Competing regulatory objectives—safety and civil rights—were not successfully integrated during the initial rollout of genomic civil-rights regulations after 2008. Federal law clarifies how to prioritize safety and civil rights when the two come into conflict, although with careful policy design, the two need not collide. This commentary opens a dialog about possible solutions to advance safety and civil rights together.

      PubDate: 2018-02-15T08:25:11Z
      DOI: 10.1016/j.ajhg.2017.12.004
  • The Expanding Landscape of Alternative Splicing Variation in Human
    • Authors: Eddie Park; Zhicheng Pan; Zijun Zhang; Lan Lin; Yi Xing
      Pages: 11 - 26
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Eddie Park, Zhicheng Pan, Zijun Zhang, Lan Lin, Yi Xing
      Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed researchers to investigate alternative splicing at an unprecedented scale and resolution. Population-scale transcriptome studies have revealed many naturally occurring genetic variants that modulate alternative splicing and consequently influence phenotypic variability and disease susceptibility in human populations. Innovations in experimental and computational tools such as massively parallel reporter assays and deep learning have enabled the rapid screening of genomic variants for their causal impacts on splicing. In this review, we describe technological advances that have greatly increased the speed and scale at which discoveries are made about the genetic variation of alternative splicing. We summarize major findings from population transcriptomic studies of alternative splicing and discuss the implications of these findings for human genetics and medicine.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.11.002
  • The Comoros Show the Earliest Austronesian Gene Flow into the Swahili
    • Authors: Nicolas Brucato; Veronica Fernandes; Stéphane Mazières; Pradiptajati Kusuma; Murray P. Cox; Joseph Wainaina Ng’ang’a; Mohammed Omar; Marie-Claude Simeone-Senelle; Coralie Frassati; Farida Alshamali; Bertrand Fin; Anne Boland; Jean-Francois Deleuze; Mark Stoneking; Alexander Adelaar; Alison Crowther; Nicole Boivin; Luisa Pereira; Pascal Bailly; Jacques Chiaroni; François-Xavier Ricaut
      Pages: 58 - 68
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Nicolas Brucato, Veronica Fernandes, Stéphane Mazières, Pradiptajati Kusuma, Murray P. Cox, Joseph Wainaina Ng’ang’a, Mohammed Omar, Marie-Claude Simeone-Senelle, Coralie Frassati, Farida Alshamali, Bertrand Fin, Anne Boland, Jean-Francois Deleuze, Mark Stoneking, Alexander Adelaar, Alison Crowther, Nicole Boivin, Luisa Pereira, Pascal Bailly, Jacques Chiaroni, François-Xavier Ricaut
      At the dawn of the second millennium, the expansion of the Indian Ocean trading network aligned with the emergence of an outward-oriented community along the East African coast to create a cosmopolitan cultural and trading zone known as the Swahili Corridor. On the basis of analyses of new genome-wide genotyping data and uniparental data in 276 individuals from coastal Kenya and the Comoros islands, along with large-scale genetic datasets from the Indian Ocean rim, we reconstruct historical population dynamics to show that the Swahili Corridor is largely an eastern Bantu genetic continuum. Limited gene flows from the Middle East can be seen in Swahili and Comorian populations at dates corresponding to historically documented contacts. However, the main admixture event in southern insular populations, particularly Comorian and Malagasy groups, occurred with individuals from Island Southeast Asia as early as the 8th century, reflecting an earlier dispersal from this region. Remarkably, our results support recent archaeological and linguistic evidence-based suggestions that the Comoros archipelago was the earliest location of contact between Austronesian and African populations in the Swahili Corridor.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.11.011
  • Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD
           and Assessment of Age-Specific Effects
    • Authors: Carolina Medina-Gomez; John P. Kemp; Katerina Trajanoska; Jian’an Luan; Alessandra Chesi; Tarunveer S. Ahluwalia; Dennis O. Mook-Kanamori; Annelies Ham; Fernando P. Hartwig; Daniel S. Evans; Raimo Joro; Ivana Nedeljkovic; Hou-Feng Zheng; Kun Zhu; Mustafa Atalay; Ching-Ti Liu; Maria Nethander; Linda Broer; Gudmar Porleifsson; Benjamin H. Mullin; Samuel K. Handelman; Mike A. Nalls; Leon E. Jessen; Denise H.M. Heppe; J. Brent Richards; Carol Wang; Bo Chawes; Katharina E. Schraut; Najaf Amin; Nick Wareham; David Karasik; Nathalie Van der Velde; M. Arfan Ikram; Babette S. Zemel; Yanhua Zhou; Christian J. Carlsson; Yongmei Liu; Fiona E. McGuigan; Cindy G. Boer; Klaus Bønnelykke; Stuart H. Ralston; John A. Robbins; John P. Walsh; M. Carola Zillikens; Claudia Langenberg; Ruifang Li-Gao; Frances M.K. Williams; Tamara B. Harris; Kristina Akesson; Rebecca D. Jackson; Gunnar Sigurdsson; Martin den Heijer; Bram C.J. van der Eerden; Jeroen van de Peppel; Timothy D. Spector; Craig Pennell; Bernardo L. Horta; Janine F. Felix; Jing Hua Zhao; Scott G. Wilson; Renée de Mutsert; Hans Bisgaard; Unnur Styrkársdóttir; Vincent W. Jaddoe; Eric Orwoll; Timo A. Lakka; Robert Scott; Struan F.A. Grant; Mattias Lorentzon; Cornelia M. van Duijn; James F. Wilson; Kari Stefansson; Bruce M. Psaty; Douglas P. Kiel; Claes Ohlsson; Evangelia Ntzani; Andre J. van Wijnen; Vincenzo Forgetta; Mohsen Ghanbari; John G. Logan; Graham R. Williams; J.H. Duncan Bassett; Peter I. Croucher; Evangelos Evangelou; Andre G. Uitterlinden; Cheryl L. Ackert-Bicknell; Jonathan H. Tobias; David M. Evans; Fernando Rivadeneira
      Pages: 88 - 102
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Carolina Medina-Gomez, John P. Kemp, Katerina Trajanoska, Jian’an Luan, Alessandra Chesi, Tarunveer S. Ahluwalia, Dennis O. Mook-Kanamori, Annelies Ham, Fernando P. Hartwig, Daniel S. Evans, Raimo Joro, Ivana Nedeljkovic, Hou-Feng Zheng, Kun Zhu, Mustafa Atalay, Ching-Ti Liu, Maria Nethander, Linda Broer, Gudmar Porleifsson, Benjamin H. Mullin, Samuel K. Handelman, Mike A. Nalls, Leon E. Jessen, Denise H.M. Heppe, J. Brent Richards, Carol Wang, Bo Chawes, Katharina E. Schraut, Najaf Amin, Nick Wareham, David Karasik, Nathalie Van der Velde, M. Arfan Ikram, Babette S. Zemel, Yanhua Zhou, Christian J. Carlsson, Yongmei Liu, Fiona E. McGuigan, Cindy G. Boer, Klaus Bønnelykke, Stuart H. Ralston, John A. Robbins, John P. Walsh, M. Carola Zillikens, Claudia Langenberg, Ruifang Li-Gao, Frances M.K. Williams, Tamara B. Harris, Kristina Akesson, Rebecca D. Jackson, Gunnar Sigurdsson, Martin den Heijer, Bram C.J. van der Eerden, Jeroen van de Peppel, Timothy D. Spector, Craig Pennell, Bernardo L. Horta, Janine F. Felix, Jing Hua Zhao, Scott G. Wilson, Renée de Mutsert, Hans Bisgaard, Unnur Styrkársdóttir, Vincent W. Jaddoe, Eric Orwoll, Timo A. Lakka, Robert Scott, Struan F.A. Grant, Mattias Lorentzon, Cornelia M. van Duijn, James F. Wilson, Kari Stefansson, Bruce M. Psaty, Douglas P. Kiel, Claes Ohlsson, Evangelia Ntzani, Andre J. van Wijnen, Vincenzo Forgetta, Mohsen Ghanbari, John G. Logan, Graham R. Williams, J.H. Duncan Bassett, Peter I. Croucher, Evangelos Evangelou, Andre G. Uitterlinden, Cheryl L. Ackert-Bicknell, Jonathan H. Tobias, David M. Evans, Fernando Rivadeneira
      Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.005
  • Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of
           Intracranial Aneurysm
    • Authors: Romain Bourcier; Solena Le Scouarnec; Stéphanie Bonnaud; Matilde Karakachoff; Emmanuelle Bourcereau; Sandrine Heurtebise-Chrétien; Céline Menguy; Christian Dina; Floriane Simonet; Alexis Moles; Cédric Lenoble; Pierre Lindenbaum; Stéphanie Chatel; Bertrand Isidor; Emmanuelle Génin; Jean-François Deleuze; Jean-Jacques Schott; Hervé Le Marec; Gervaise Loirand; Hubert Desal; Richard Redon; Hubert Desal; Romain Bourcier; Benjamin Daumas-Duport; Bertrand Isidor; Jérôme Connault; Pierre Lebranchu; Thierry Le Tourneau; Marie Pierre Viarouge; Chrisanthi Papagiannaki; Michel Piotin; Hocine Redjem; Mikael Mazighi; Jean Philippe Desilles; Olivier Naggara; Denis Trystram; Myriam Edjlali-Goujon; Christine Rodriguez; Waghi Ben Hassen; Suzanna Saleme; Charbel Mounayer; Olivier Levrier; Pierre Aguettaz; Xavier Combaz; Anne Pasco; Emeline Berthier; Marc Bintner; Marc Molho; Pascale Gauthier; Cyril Chivot; Vincent Costalat; Cyril Darganzil; Alain Bonafé; Anne Christine Januel; Caterina Michelozzi; Christophe Cognard; Fabrice Bonneville; Philippe Tall; Jean Darcourt; Alessandra Biondi; Cristina Iosif; Elisa Pomero; Jean Christophe Ferre; Jean Yves Gauvrit; François Eugene; Hélène Raoult; Jean Christophe Gentric; Julien Ognard; René Anxionnat; Serge Bracard; Anne Laure Derelle; Romain Tonnelet; Laurent Spelle; Léon Ikka; Robert Fahed; Aymeric Rouchaud; Augustin Ozanne; Jildaz Caroff; Nidal Ben Achour; Jacques Moret; Emmanuel Chabert; Jérôme Berge; Gaultier Marnat; Xavier Barreau; Florent Gariel; Frédéric Clarencon; Mohammed Aggour; Frédéric Ricolfi; Adrien Chavent; Pierre Thouant; Pablo Lebidinsky; Brivael Lemogne; Denis Herbreteau; Richard Bibi; Laurent Pierot; Sébastien Soize; Marc Antoine Labeyrie; Christophe Vandendries; Emmanuel Houdart; Appoline Kazemi; Xavier Leclerc; Jean Pierre Pruvo; Sophie Gallas; Stéphane Velasco
      Pages: 133 - 141
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Romain Bourcier, Solena Le Scouarnec, Stéphanie Bonnaud, Matilde Karakachoff, Emmanuelle Bourcereau, Sandrine Heurtebise-Chrétien, Céline Menguy, Christian Dina, Floriane Simonet, Alexis Moles, Cédric Lenoble, Pierre Lindenbaum, Stéphanie Chatel, Bertrand Isidor, Emmanuelle Génin, Jean-François Deleuze, Jean-Jacques Schott, Hervé Le Marec, Gervaise Loirand, Hubert Desal, Richard Redon
      Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)—which encodes a circulating pro-angiogenic factor mainly secreted from the liver—shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.006
  • A Comprehensive Workflow for Read Depth-Based Identification of
           Copy-Number Variation from Whole-Genome Sequence Data
    • Authors: Brett Trost; Susan Walker; Zhuozhi Wang; Bhooma Thiruvahindrapuram; Jeffrey R. MacDonald; Wilson W.L. Sung; Sergio L. Pereira; Joe Whitney; Ada J.S. Chan; Giovanna Pellecchia; Miriam S. Reuter; Si Lok; Ryan K.C. Yuen; Christian R. Marshall; Daniele Merico; Stephen W. Scherer
      Pages: 142 - 155
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Brett Trost, Susan Walker, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Jeffrey R. MacDonald, Wilson W.L. Sung, Sergio L. Pereira, Joe Whitney, Ada J.S. Chan, Giovanna Pellecchia, Miriam S. Reuter, Si Lok, Ryan K.C. Yuen, Christian R. Marshall, Daniele Merico, Stephen W. Scherer
      A remaining hurdle to whole-genome sequencing (WGS) becoming a first-tier genetic test has been accurate detection of copy-number variations (CNVs). Here, we used several datasets to empirically develop a detailed workflow for identifying germline CNVs >1 kb from short-read WGS data using read depth-based algorithms. Our workflow is comprehensive in that it addresses all stages of the CNV-detection process, including DNA library preparation, sequencing, quality control, reference mapping, and computational CNV identification. We used our workflow to detect rare, genic CNVs in individuals with autism spectrum disorder (ASD), and 120/120 such CNVs tested using orthogonal methods were successfully confirmed. We also identified 71 putative genic de novo CNVs in this cohort, which had a confirmation rate of 70%; the remainder were incorrectly identified as de novo due to false positives in the proband (7%) or parental false negatives (23%). In individuals with an ASD diagnosis in which both microarray and WGS experiments were performed, our workflow detected all clinically relevant CNVs identified by microarrays, as well as additional potentially pathogenic CNVs < 20 kb. Thus, CNVs of clinical relevance can be discovered from WGS with a detection rate exceeding microarrays, positioning WGS as a single assay for genetic variation detection.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.007
  • Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and
           Clinical Genetic Variant Classification in Neurodevelopmental Syndromes
    • Authors: Erfan Aref-Eshghi; David I. Rodenhiser; Laila C. Schenkel; Hanxin Lin; Cindy Skinner; Peter Ainsworth; Guillaume Paré; Rebecca L. Hood; Dennis E. Bulman; Kristin D. Kernohan; Kym M. Boycott; Philippe M. Campeau; Charles Schwartz; Bekim Sadikovic
      Pages: 156 - 174
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Erfan Aref-Eshghi, David I. Rodenhiser, Laila C. Schenkel, Hanxin Lin, Cindy Skinner, Peter Ainsworth, Guillaume Paré, Rebecca L. Hood, Dennis E. Bulman, Kristin D. Kernohan, Kym M. Boycott, Philippe M. Campeau, Charles Schwartz, Bekim Sadikovic
      Pediatric developmental syndromes present with systemic, complex, and often overlapping clinical features that are not infrequently a consequence of Mendelian inheritance of mutations in genes involved in DNA methylation, establishment of histone modifications, and chromatin remodeling (the “epigenetic machinery”). The mechanistic cross-talk between histone modification and DNA methylation suggests that these syndromes might be expected to display specific DNA methylation signatures that are a reflection of those primary errors associated with chromatin dysregulation. Given the interrelated functions of these chromatin regulatory proteins, we sought to identify DNA methylation epi-signatures that could provide syndrome-specific biomarkers to complement standard clinical diagnostics. In the present study, we examined peripheral blood samples from a large cohort of individuals encompassing 14 Mendelian disorders displaying mutations in the genes encoding proteins of the epigenetic machinery. We demonstrated that specific but partially overlapping DNA methylation signatures are associated with many of these conditions. The degree of overlap among these epi-signatures is minimal, further suggesting that, consistent with the initial event, the downstream changes are unique to every syndrome. In addition, by combining these epi-signatures, we have demonstrated that a machine learning tool can be built to concurrently screen for multiple syndromes with high sensitivity and specificity, and we highlight the utility of this tool in solving ambiguous case subjects presenting with variants of unknown significance, along with its ability to generate accurate predictions for subjects presenting with the overlapping clinical and molecular features associated with the disruption of the epigenetic machinery.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.008
  • Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation
           with Defective Fucosylation
    • Authors: Bobby G. Ng; Gege Xu; Nandini Chandy; Joan Steyermark; Deepali N. Shinde; Kelly Radtke; Kimiyo Raymond; Carlito B. Lebrilla; Ali AlAsmari; Sharon F. Suchy; Zöe Powis; Eissa Ali Faqeih; Susan A. Berry; David F. Kronn; Hudson H. Freeze
      Pages: 188 - 195
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Bobby G. Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N. Shinde, Kelly Radtke, Kimiyo Raymond, Carlito B. Lebrilla, Ali AlAsmari, Sharon F. Suchy, Zöe Powis, Eissa Ali Faqeih, Susan A. Berry, David F. Kronn, Hudson H. Freeze
      Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as “core fucosylation.” Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239∗), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315∗). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8 −/− knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.009
  • De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a
           Neurodevelopmental Disorder
    • Authors: Davor Lessel; Claudia Schob; Sébastien Küry; Margot R.F. Reijnders; Tamar Harel; Mohammad K. Eldomery; Zeynep Coban-Akdemir; Jonas Denecke; Shimon Edvardson; Estelle Colin; Alexander P.A. Stegmann; Erica H. Gerkes; Marine Tessarech; Dominique Bonneau; Magalie Barth; Thomas Besnard; Benjamin Cogné; Anya Revah-Politi; Tim M. Strom; Jill A. Rosenfeld; Yaping Yang; Jennifer E. Posey; LaDonna Immken; Nelly Oundjian; Katherine L. Helbig; Naomi Meeks; Kelsey Zegar; Jenny Morton; the DDD study; Jolanda H. Schieving; Ana Claasen; Matthew Huentelman; Vinodh Narayanan; Keri Ramsey; Han G. Brunner; Orly Elpeleg; Sandra Mercier; Stéphane Bézieau; Christian Kubisch; Tjitske Kleefstra; Stefan Kindler; James R. Lupski; Hans-Jürgen Kreienkamp
      First page: 196
      Abstract: Publication date: 4 January 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 1
      Author(s): Davor Lessel, Claudia Schob, Sébastien Küry, Margot R.F. Reijnders, Tamar Harel, Mohammad K. Eldomery, Zeynep Coban-Akdemir, Jonas Denecke, Shimon Edvardson, Estelle Colin, Alexander P.A. Stegmann, Erica H. Gerkes, Marine Tessarech, Dominique Bonneau, Magalie Barth, Thomas Besnard, Benjamin Cogné, Anya Revah-Politi, Tim M. Strom, Jill A. Rosenfeld, Yaping Yang, Jennifer E. Posey, LaDonna Immken, Nelly Oundjian, Katherine L. Helbig, Naomi Meeks, Kelsey Zegar, Jenny Morton, the DDD study, Jolanda H. Schieving, Ana Claasen, Matthew Huentelman, Vinodh Narayanan, Keri Ramsey, Han G. Brunner, Orly Elpeleg, Sandra Mercier, Stéphane Bézieau, Christian Kubisch, Tjitske Kleefstra, Stefan Kindler, James R. Lupski, Hans-Jürgen Kreienkamp

      PubDate: 2018-01-09T16:03:52Z
      DOI: 10.1016/j.ajhg.2017.12.016
  • Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes
    • Authors: Simone Martinelli; Oliver H.F. Krumbach; Francesca Pantaleoni; Simona Coppola; Ehsan Amin; Luca Pannone; Kazem Nouri; Luciapia Farina; Radovan Dvorsky; Francesca Lepri; Marcel Buchholzer; Raphael Konopatzki; Laurence Walsh; Katelyn Payne; Mary Ella Pierpont; Samantha Schrier Vergano; Katherine G. Langley; Douglas Larsen; Kelly D. Farwell; Sha Tang; Cameron Mroske; Ivan Gallotta; Elia Di Schiavi; Matteo della Monica; Licia Lugli; Cesare Rossi; Marco Seri; Guido Cocchi; Lindsay Henderson; Berivan Baskin; Mariëlle Alders; Roberto Mendoza-Londono; Lucie Dupuis; Deborah A. Nickerson; Jessica X. Chong; Naomi Meeks; Kathleen Brown; Tahnee Causey; Megan T. Cho; Stephanie Demuth; Maria Cristina Digilio; Bruce D. Gelb; Michael J. Bamshad; Martin Zenker; Mohammad Reza Ahmadian; Raoul C. Hennekam; Marco Tartaglia; Ghayda M. Mirzaa
      Abstract: Publication date: Available online 25 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Simone Martinelli, Oliver H.F. Krumbach, Francesca Pantaleoni, Simona Coppola, Ehsan Amin, Luca Pannone, Kazem Nouri, Luciapia Farina, Radovan Dvorsky, Francesca Lepri, Marcel Buchholzer, Raphael Konopatzki, Laurence Walsh, Katelyn Payne, Mary Ella Pierpont, Samantha Schrier Vergano, Katherine G. Langley, Douglas Larsen, Kelly D. Farwell, Sha Tang, Cameron Mroske, Ivan Gallotta, Elia Di Schiavi, Matteo della Monica, Licia Lugli, Cesare Rossi, Marco Seri, Guido Cocchi, Lindsay Henderson, Berivan Baskin, Mariëlle Alders, Roberto Mendoza-Londono, Lucie Dupuis, Deborah A. Nickerson, Jessica X. Chong, Naomi Meeks, Kathleen Brown, Tahnee Causey, Megan T. Cho, Stephanie Demuth, Maria Cristina Digilio, Bruce D. Gelb, Michael J. Bamshad, Martin Zenker, Mohammad Reza Ahmadian, Raoul C. Hennekam, Marco Tartaglia, Ghayda M. Mirzaa
      Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.015
  • Assessment of the Clinical Relevance of BRCA2 Missense Variants by
           Functional and Computational Approaches
    • Authors: Lucia Guidugli; Hermela Shimelis; David L. Masica; Vernon S. Pankratz; Gary B. Lipton; Namit Singh; Chunling Hu; Alvaro N.A. Monteiro; Noralane M. Lindor; David E. Goldgar; Rachel Karchin; Edwin S. Iversen; Fergus J. Couch
      Abstract: Publication date: Available online 25 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Lucia Guidugli, Hermela Shimelis, David L. Masica, Vernon S. Pankratz, Gary B. Lipton, Namit Singh, Chunling Hu, Alvaro N.A. Monteiro, Noralane M. Lindor, David E. Goldgar, Rachel Karchin, Edwin S. Iversen, Fergus J. Couch
      Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ≥99% probability of pathogenicity, and 73 had ≥95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly (p < 0.05) over-predicted pathogenic variants. We subsequently combined functional and Align-GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the overall probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, we used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay. Together, the results show that systematic functional assays in combination with in silico predictors of pathogenicity provide robust tools for clinical annotation of BRCA2 VUS.

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.013
  • Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu
    • Authors: Yohann Jourdy; Alexandre Janin; Mathilde Fretigny; Anne Lienhart; Claude Négrier; Dominique Bozon; Christine Vinciguerra
      Abstract: Publication date: Available online 18 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude Négrier, Dominique Bozon, Christine Vinciguerra
      Incorporation of distant intronic sequences in mature mRNA is an underappreciated cause of genetic disease. Several disease-causing pseudoexons have been found to contain repetitive elements such as Alu elements. This study describes an original pathological mechanism by which a small intronic deletion leads to Alu exonization. We identified an intronic deletion, c.2113+461_2113+473del, in the F8 intron 13, in two individuals with mild hemophilia A. In vivo and in vitro transcript analysis found an aberrant transcript, with an insertion of a 122-bp intronic fragment (c.2113_2114ins2113+477_2113+598) at the exon 13–14 junction. This out-of-frame insertion is predicted to lead to truncated protein (p.Gly705Aspfs∗37). DNA sequencing analysis found that the pseudoexon corresponds to antisense AluY element and the deletion removed a part of the poly(T)-tail from the right arm of these AluY. The heterogenous nuclear riboprotein C1/C2 (hnRNP C) is an important antisense Alu-derived cryptic exon silencer and binds to poly(T)-tracts. Disruption of the hnRNP C binding site in AluY T-tract by mutagenesis or hnRNP C knockdown using siRNA in HeLa cells reproduced the effect of c.2113+461_2113+473del. The screening of 114 unrelated families with mild hemophilia A in whom no genetic event was previously identified found a deletion in the poly(T)-tail of AluY in intron 13 in 54% of case subjects (n = 61/114). In conclusion, this study describes a deletion leading to Alu exonization found in 6.1% of families with mild hemophila A in France.

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.010
  • Evolutionary Rewiring of Human Regulatory Networks by Waves of Genome
    • Authors: Davide Marnetto; Federica Mantica; Ivan Molineris; Elena Grassi; Igor Pesando; Paolo Provero
      Abstract: Publication date: Available online 18 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Davide Marnetto, Federica Mantica, Ivan Molineris, Elena Grassi, Igor Pesando, Paolo Provero
      Genome expansion is believed to be an important driver of the evolution of gene regulation. To investigate the role of a newly arising sequence in rewiring regulatory networks, we estimated the age of each region of the human genome by applying maximum parsimony to genome-wide alignments with 100 vertebrates. We then studied the age distribution of several types of functional regions, with a focus on regulatory elements. The age distribution of regulatory elements reveals the extensive use of newly formed genomic sequence in the evolution of regulatory interactions. Many transcription factors have expanded their repertoire of targets through waves of genomic expansions that can be traced to specific evolutionary times. Repeated elements contributed a major part of such expansion: many classes of such elements are enriched in binding sites of one or a few specific transcription factors, whose binding sites are localized in specific portions of the element and characterized by distinctive motif words. These features suggest that the binding sites were available as soon as the new sequence entered the genome, rather than being created later by accumulation of point mutations. By comparing the age of regulatory regions to the evolutionary shift in expression of nearby genes, we show that rewiring through genome expansion played an important role in shaping human regulatory networks.

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.014
  • Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in
    • Authors: Chi-Fan Yang; Shuan-Pei Lin; Chien-Ping Chiang; Yu-Hung Wu; Weng Siong H’ng; Chun-Ping Chang; Yuan-Tsong Chen; Jer-Yuarn Wu
      Abstract: Publication date: Available online 11 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Chi-Fan Yang, Shuan-Pei Lin, Chien-Ping Chiang, Yu-Hung Wu, Weng Siong H’ng, Chun-Ping Chang, Yuan-Tsong Chen, Jer-Yuarn Wu
      Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.012
  • KIAA1109 Variants Are Associated with a Severe Disorder of Brain
           Development and Arthrogryposis
    • Authors: Lucie Gueneau; Richard Fish Hanan Shamseldin Norine Voisin Tran Mau-Them
      Abstract: Publication date: Available online 28 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Lucie Gueneau, Richard J. Fish, Hanan E. Shamseldin, Norine Voisin, Frédéric Tran Mau-Them, Egle Preiksaitiene, Glen R. Monroe, Angeline Lai, Audrey Putoux, Fabienne Allias, Qamariya Ambusaidi, Laima Ambrozaityte, Loreta Cimbalistienė, Julien Delafontaine, Nicolas Guex, Mais Hashem, Wesam Kurdi, Saumya Shekhar Jamuar, Lim J. Ying, Carine Bonnard, Tommaso Pippucci, Sylvain Pradervand, Bernd Roechert, Peter M. van Hasselt, Michaël Wiederkehr, Caroline F. Wright, Ioannis Xenarios, Gijs van Haaften, Charles Shaw-Smith, Erica M. Schindewolf, Marguerite Neerman-Arbez, Damien Sanlaville, Gaëtan Lesca, Laurent Guibaud, Bruno Reversade, Jamel Chelly, Vaidutis Kučinskas, Fowzan S. Alkuraya, Alexandre Reymond
      Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands’ features.

      PubDate: 2018-01-04T15:41:28Z
  • Genotype-Phenotype Correlation in NF1: Evidence for a More Severe
           Phenotype Associated with Missense Mutations Affecting NF1 Codons
    • Authors: Magdalena Koczkowska; Yunjia Chen Tom Callens Alicia Gomes Angela Sharp
      Abstract: Publication date: Available online 28 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Magdalena Koczkowska, Yunjia Chen, Tom Callens, Alicia Gomes, Angela Sharp, Sherrell Johnson, Meng-Chang Hsiao, Zhenbin Chen, Meena Balasubramanian, Christopher P. Barnett, Troy A. Becker, Shay Ben-Shachar, Debora R. Bertola, Jaishri O. Blakeley, Emma M.M. Burkitt-Wright, Alison Callaway, Melissa Crenshaw, Karin S. Cunha, Mitch Cunningham, Maria D. D’Agostino, Karin Dahan, Alessandro De Luca, Anne Destrée, Radhika Dhamija, Marica Eoli, D. Gareth R. Evans, Patricia Galvin-Parton, Jaya K. George-Abraham, Karen W. Gripp, Jose Guevara-Campos, Neil A. Hanchard, Concepcion Hernández-Chico, LaDonna Immken, Sandra Janssens, Kristi J. Jones, Beth A. Keena, Aaina Kochhar, Jan Liebelt, Arelis Martir-Negron, Maurice J. Mahoney, Isabelle Maystadt, Carey McDougall, Meriel McEntagart, Nancy Mendelsohn, David T. Miller, Geert Mortier, Jenny Morton, John Pappas, Scott R. Plotkin, Dinel Pond, Kenneth Rosenbaum, Karol Rubin, Laura Russell, Lane S. Rutledge, Veronica Saletti, Rhonda Schonberg, Allison Schreiber, Meredith Seidel, Elizabeth Siqveland, David W. Stockton, Eva Trevisson, Nicole J. Ullrich, Meena Upadhyaya, Rick van Minkelen, Helene Verhelst, Margaret R. Wallace, Yoon-Sim Yap, Elaine Zackai, Jonathan Zonana, Vickie Zurcher, Kathleen Claes, Yolanda Martin, Bruce R. Korf, Eric Legius, Ludwine M. Messiaen
      Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

      PubDate: 2018-01-04T15:41:28Z
  • Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and
           Highlights Biological Pathways and Regulatory Elements Involved in Cardiac
    • Authors: Jonas Nielsen; Lars Fritsche Wei Zhou Tanya Teslovich Oddgeir Holmen
      Abstract: Publication date: Available online 28 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Jonas B. Nielsen, Lars G. Fritsche, Wei Zhou, Tanya M. Teslovich, Oddgeir L. Holmen, Stefan Gustafsson, Maiken E. Gabrielsen, Ellen M. Schmidt, Robin Beaumont, Brooke N. Wolford, Maoxuan Lin, Chad M. Brummett, Michael H. Preuss, Lena Refsgaard, Erwin P. Bottinger, Sarah E. Graham, Ida Surakka, Yunhan Chu, Anne Heidi Skogholt, Håvard Dalen, Alan P. Boyle, Hakan Oral, Todd J. Herron, Jacob Kitzman, José Jalife, Jesper H. Svendsen, Morten S. Olesen, Inger Njølstad, Maja-Lisa Løchen, Aris Baras, Omri Gottesman, Anthony Marcketta, Colm O’Dushlaine, Marylyn D. Ritchie, Tom Wilsgaard, Ruth J.F. Loos, Timothy M. Frayling, Michael Boehnke, Erik Ingelsson, David J. Carey, Frederick E. Dewey, Hyun M. Kang, Gonçalo R. Abecasis, Kristian Hveem, Cristen J. Willer
      Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

      PubDate: 2018-01-04T15:41:28Z
  • So Long, and Thanks for All the Genes!
    • Authors: David L. Nelson
      Pages: 871 - 873
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): David L. Nelson

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.012
  • A Selection Operator for Summary Association Statistics Reveals Allelic
           Heterogeneity of Complex Traits
    • Authors: Zheng Ning; Youngjo Lee; Peter K. Joshi; James F. Wilson; Yudi Pawitan; Xia Shen
      Pages: 903 - 912
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Zheng Ning, Youngjo Lee, Peter K. Joshi, James F. Wilson, Yudi Pawitan, Xia Shen
      In recent years, as a secondary analysis in genome-wide association studies (GWASs), conditional and joint multiple-SNP analysis (GCTA-COJO) has been successful in allowing the discovery of additional association signals within detected loci. This suggests that many loci mapped in GWASs harbor more than a single causal variant. In order to interpret the underlying mechanism regulating a complex trait of interest in each discovered locus, researchers must assess the magnitude of allelic heterogeneity within the locus. We developed a penalized selection operator for jointly analyzing multiple variants (SOJO) within each mapped locus on the basis of LASSO (least absolute shrinkage and selection operator) regression derived from summary association statistics. We found that, compared to stepwise conditional multiple-SNP analysis, SOJO provided better sensitivity and specificity in predicting the number of alleles associated with complex traits in each locus. SOJO suggested causal variants potentially missed by GCTA-COJO. Compared to using top variants from genome-wide significant loci in GWAS, using SOJO increased the proportion of variance prediction for height by 65% without additional discovery samples or additional loci in the genome. Our empirical results indicate that human height is not only a highly polygenic trait, but also has high allelic heterogeneity within its established hundreds of loci.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.09.027
  • Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass
           Index Distribution
    • Authors: Arkan Abadi; Akram Alyass; Sebastien Robiou du Pont; Ben Bolker; Pardeep Singh; Viswanathan Mohan; Rafael Diaz; James C. Engert; Salim Yusuf; Hertzel C. Gerstein; Sonia S. Anand; David Meyre
      Pages: 925 - 938
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Arkan Abadi, Akram Alyass, Sebastien Robiou du Pont, Ben Bolker, Pardeep Singh, Viswanathan Mohan, Rafael Diaz, James C. Engert, Salim Yusuf, Hertzel C. Gerstein, Sonia S. Anand, David Meyre
      A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)—rs1421085 (FTO; p = 8.69 × 10−15), rs6235 (PCSK1; p = 7.11 × 10−6), rs7903146 (TCF7L2; p = 9.60 × 10−6), rs11873305 (MC4R; p = 5.08 × 10−5), rs12617233 (FANCL; p = 5.30 × 10−5), rs11672660 (GIPR; p = 1.64 × 10−4), rs997295 (MAP2K5; p = 3.25 × 10−4), rs6499653 (FTO; p = 6.23 × 10−4), and rs3824755 (NT5C2; p = 7.90 × 10−4)—increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one (<1%), rs6219 (IGF1, p = 1.80 × 10−4), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p = 7.03 × 10−37; height: p = 0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.10.007
  • Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes
           Zellweger Spectrum Disorder
    • Authors: Kim D. Falkenberg; Nancy E. Braverman; Ann B. Moser; Steven J. Steinberg; Femke C.C. Klouwer; Agatha Schlüter; Montserrat Ruiz; Aurora Pujol; Martin Engvall; Karin Naess; FrancJan van Spronsen; Irene Körver-Keularts; M. Estela Rubio-Gozalbo; Sacha Ferdinandusse; Ronald J.A. Wanders; Hans R. Waterham
      Pages: 965 - 976
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Kim D. Falkenberg, Nancy E. Braverman, Ann B. Moser, Steven J. Steinberg, Femke C.C. Klouwer, Agatha Schlüter, Montserrat Ruiz, Aurora Pujol, Martin Engvall, Karin Naess, FrancJan van Spronsen, Irene Körver-Keularts, M. Estela Rubio-Gozalbo, Sacha Ferdinandusse, Ronald J.A. Wanders, Hans R. Waterham
      Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3′ untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3′ UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.007
  • De Novo Variants in GRIA4 Lead to Intellectual Disability with or without
           Seizures and Gait Abnormalities
    • Authors: Sonja Martin; Adam Chamberlin; Deepali N. Shinde; Maja Hempel; Tim M. Strom; Allison Schreiber; Jessika Johannsen; Lilian Bomme Ousager; Martin J. Larsen; Lars Kjaersgaard Hansen; Ali Fatemi; Julie S. Cohen; Johannes Lemke; Kristina P. Sørensen; Katherine L. Helbig; Davor Lessel; Rami Abou Jamra
      Pages: 1013 - 1020
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sonja Martin, Adam Chamberlin, Deepali N. Shinde, Maja Hempel, Tim M. Strom, Allison Schreiber, Jessika Johannsen, Lilian Bomme Ousager, Martin J. Larsen, Lars Kjaersgaard Hansen, Ali Fatemi, Julie S. Cohen, Johannes Lemke, Kristina P. Sørensen, Katherine L. Helbig, Davor Lessel, Rami Abou Jamra
      Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.004
  • ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental
    • Authors: Sara Cuvertino; Helen M. Stuart; Kate E. Chandler; Neil A. Roberts; Ruth Armstrong; Laura Bernardini; Sanjeev Bhaskar; Bert Callewaert; Jill Clayton-Smith; Cristina Hernando Davalillo; Charu Deshpande; Koenraad Devriendt; Maria C. Digilio; Abhijit Dixit; Matthew Edwards; Jan M. Friedman; Antonio Gonzalez-Meneses; Shelagh Joss; Bronwyn Kerr; Anne Katrin Lampe; Sylvie Langlois; Rachel Lennon; Philippe Loget; David Y.T. Ma; Ruth McGowan; Maryse Des Medt; James O’Sullivan; Sylvie Odent; Michael J. Parker; Céline Pebrel-Richard; Florence Petit; Zornitza Stark; Sylvia Stockler-Ipsiroglu; Sigrid Tinschert; Pradeep Vasudevan; Olaya Villa; Susan M. White; Farah R. Zahir; Adrian S. Woolf; Siddharth Banka
      Pages: 1021 - 1033
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sara Cuvertino, Helen M. Stuart, Kate E. Chandler, Neil A. Roberts, Ruth Armstrong, Laura Bernardini, Sanjeev Bhaskar, Bert Callewaert, Jill Clayton-Smith, Cristina Hernando Davalillo, Charu Deshpande, Koenraad Devriendt, Maria C. Digilio, Abhijit Dixit, Matthew Edwards, Jan M. Friedman, Antonio Gonzalez-Meneses, Shelagh Joss, Bronwyn Kerr, Anne Katrin Lampe, Sylvie Langlois, Rachel Lennon, Philippe Loget, David Y.T. Ma, Ruth McGowan, Maryse Des Medt, James O’Sullivan, Sylvie Odent, Michael J. Parker, Céline Pebrel-Richard, Florence Petit, Zornitza Stark, Sylvia Stockler-Ipsiroglu, Sigrid Tinschert, Pradeep Vasudevan, Olaya Villa, Susan M. White, Farah R. Zahir, Adrian S. Woolf, Siddharth Banka
      ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.006
  • Exome-wide Association Study Identifies GREB1L Mutations in Congenital
           Kidney Malformations
    • Authors: Simone Sanna-Cherchi; Kamal Khan; Rik Westland; Priya Krithivasan; Lorraine Fievet; Hila Milo Rasouly; Iuliana Ionita-Laza; Valentina P. Capone; David A. Fasel; Krzysztof Kiryluk; Sitharthan Kamalakaran; Monica Bodria; Edgar A. Otto; Matthew G. Sampson; Christopher E. Gillies; Virginia Vega-Warner; Katarina Vukojevic; Igor Pediaditakis; Gabriel S. Makar; Adele Mitrotti; Miguel Verbitsky; Jeremiah Martino; Qingxue Liu; Young-Ji Na; Vinicio Goj; Gianluigi Ardissino; Maddalena Gigante; Loreto Gesualdo; Magdalena Janezcko; Marcin Zaniew; Cathy Lee Mendelsohn; Shirlee Shril; Friedhelm Hildebrandt; Joanna A.E. van Wijk; Adela Arapovic; Marijan Saraga; Landino Allegri; Claudia Izzi; Francesco Scolari; Velibor Tasic; Gian Marco Ghiggeri; Anna Latos-Bielenska; Anna Materna-Kiryluk; Shrikant Mane; David B. Goldstein; Richard P. Lifton; Nicholas Katsanis; Erica E. Davis; Ali G. Gharavi
      First page: 1034
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Simone Sanna-Cherchi, Kamal Khan, Rik Westland, Priya Krithivasan, Lorraine Fievet, Hila Milo Rasouly, Iuliana Ionita-Laza, Valentina P. Capone, David A. Fasel, Krzysztof Kiryluk, Sitharthan Kamalakaran, Monica Bodria, Edgar A. Otto, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Katarina Vukojevic, Igor Pediaditakis, Gabriel S. Makar, Adele Mitrotti, Miguel Verbitsky, Jeremiah Martino, Qingxue Liu, Young-Ji Na, Vinicio Goj, Gianluigi Ardissino, Maddalena Gigante, Loreto Gesualdo, Magdalena Janezcko, Marcin Zaniew, Cathy Lee Mendelsohn, Shirlee Shril, Friedhelm Hildebrandt, Joanna A.E. van Wijk, Adela Arapovic, Marijan Saraga, Landino Allegri, Claudia Izzi, Francesco Scolari, Velibor Tasic, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Shrikant Mane, David B. Goldstein, Richard P. Lifton, Nicholas Katsanis, Erica E. Davis, Ali G. Gharavi

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.003
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 691 - 692
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.04.009
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 693 - 694
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Kathryn B. Garber

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.04.006
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 1 - 2
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2016.12.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 3 - 4
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Kathryn B. Garber

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2016.12.005
  • WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow
    • Authors: Janson J. White; Juliana F. Mazzeu; Zeynep Coban-Akdemir; Yavuz Bayram; Vahid Bahrambeigi; Alexander Hoischen; Bregje W.M. van Bon; Alper Gezdirici; Elif Yilmaz Gulec; Francis Ramond; Renaud Touraine; Julien Thevenon; Marwan Shinawi; Erin Beaver; Jennifer Heeley; Julie Hoover-Fong; Ceren D. Durmaz; Halil Gurhan Karabulut; Ebru Marzioglu-Ozdemir; Atilla Cayir; Mehmet B. Duz; Mehmet Seven; Susan Price; Barbara Merfort Ferreira; Angela M. Vianna-Morgante; Sian Ellard; Andrew Parrish; Karen Stals; Josue Flores-Daboub; Shalini N. Jhangiani; Richard A. Gibbs; Han G. Brunner; V. Reid Sutton; James R. Lupski; Claudia M.B. Carvalho
      Abstract: Publication date: Available online 21 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Janson J. White, Juliana F. Mazzeu, Zeynep Coban-Akdemir, Yavuz Bayram, Vahid Bahrambeigi, Alexander Hoischen, Bregje W.M. van Bon, Alper Gezdirici, Elif Yilmaz Gulec, Francis Ramond, Renaud Touraine, Julien Thevenon, Marwan Shinawi, Erin Beaver, Jennifer Heeley, Julie Hoover-Fong, Ceren D. Durmaz, Halil Gurhan Karabulut, Ebru Marzioglu-Ozdemir, Atilla Cayir, Mehmet B. Duz, Mehmet Seven, Susan Price, Barbara Merfort Ferreira, Angela M. Vianna-Morgante, Sian Ellard, Andrew Parrish, Karen Stals, Josue Flores-Daboub, Shalini N. Jhangiani, Richard A. Gibbs, Han G. Brunner, V. Reid Sutton, James R. Lupski, Claudia M.B. Carvalho
      Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered –1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

      PubDate: 2017-12-27T14:53:53Z
      DOI: 10.1016/j.ajhg.2017.10.002
  • Histone Lysine Methylases and Demethylases in the Landscape of Human
           Developmental Disorders
    • Authors: Faundes William; Newman Laura Bernardini Natalie Canham Jill Clayton-Smith Bruno
      Abstract: Publication date: Available online 21 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka
      Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

      PubDate: 2017-12-27T14:53:53Z
  • Missense Variants in RHOBTB2 Cause a Developmental and Epileptic
           Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in
    • Authors: Jonas Straub; Enrico D.H. Konrad; Johanna Grüner; Annick Toutain; Levinus A. Bok; Megan T. Cho; Heather P. Crawford; Holly Dubbs; Ganka Douglas; Rebekah Jobling; Diana Johnson; Bryan Krock; Mohamad A. Mikati; Addie Nesbitt; Joost Nicolai; Meredith Phillips; Annapurna Poduri; Xilma R. Ortiz-Gonzalez; Zöe Powis; Avni Santani; Lacey Smith; Alexander P.A. Stegmann; Constance Stumpel; Maaike Vreeburg; Anna Fliedner; Anne Gregor; Heinrich Sticht; Christiane Zweier
      Abstract: Publication date: Available online 21 December 2017
      Source:The American Journal of Human Genetics
      Author(s): Jonas Straub, Enrico D.H. Konrad, Johanna Grüner, Annick Toutain, Levinus A. Bok, Megan T. Cho, Heather P. Crawford, Holly Dubbs, Ganka Douglas, Rebekah Jobling, Diana Johnson, Bryan Krock, Mohamad A. Mikati, Addie Nesbitt, Joost Nicolai, Meredith Phillips, Annapurna Poduri, Xilma R. Ortiz-Gonzalez, Zöe Powis, Avni Santani, Lacey Smith, Alexander P.A. Stegmann, Constance Stumpel, Maaike Vreeburg, Anna Fliedner, Anne Gregor, Heinrich Sticht, Christiane Zweier
      Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.

      PubDate: 2017-12-27T14:53:53Z
      DOI: 10.1016/j.ajhg.2017.11.008
  • A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance
           via GWAS Summary Statistics
    • Authors: Qiongshi Boyang; Derek Margret Erlendsdottir Ryan Powles Tony Jiang Yiming
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Qiongshi Lu, Boyang Li, Derek Ou, Margret Erlendsdottir, Ryan L. Powles, Tony Jiang, Yiming Hu, David Chang, Chentian Jin, Wei Dai, Qidu He, Zefeng Liu, Shubhabrata Mukherjee, Paul K. Crane, Hongyu Zhao
      Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits’ genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses, we demonstrate that our method provides accurate covariance estimates, thereby enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (Ntotal ≈ 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimer disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOAD’s correlation with cognitive traits and hints at an autoimmune component for ALS.

      PubDate: 2017-12-12T05:02:50Z
  • Mutations in TUBB4B Cause a Distinctive Sensorineural Disease
    • Authors: Romain Luscan; Sabrina Mechaussier; Antoine Paul; Guoling Tian; Xavier Gérard; Sabine Defoort-Dellhemmes; Natalie Loundon; Isabelle Audo; Sophie Bonnin; Jean-François LeGargasson; Julien Dumont; Nicolas Goudin; Meriem Garfa-Traoré; Marc Bras; Aurore Pouliet; Bettina Bessières; Nathalie Boddaert; José-Alain Sahel; Stanislas Lyonnet; Josseline Kaplan; Nicholas J. Cowan; Jean-Michel Rozet; Sandrine Marlin; Isabelle Perrault
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Romain Luscan, Sabrina Mechaussier, Antoine Paul, Guoling Tian, Xavier Gérard, Sabine Defoort-Dellhemmes, Natalie Loundon, Isabelle Audo, Sophie Bonnin, Jean-François LeGargasson, Julien Dumont, Nicolas Goudin, Meriem Garfa-Traoré, Marc Bras, Aurore Pouliet, Bettina Bessières, Nathalie Boddaert, José-Alain Sahel, Stanislas Lyonnet, Josseline Kaplan, Nicholas J. Cowan, Jean-Michel Rozet, Sandrine Marlin, Isabelle Perrault
      Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αβ-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.010
  • A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe
           Intellectual Disability without Frontonasal or Limb Malformations
    • Authors: Elizabeth E. Palmer; Raman Kumar; Christopher T. Gordon; Marie Shaw; Laurence Hubert; Renee Carroll; Marlène Rio; Lucinda Murray; Melanie Leffler; Tracy Dudding-Byth; Myriam Oufadem; Seema R. Lalani; Andrea M. Lewis; Fan Xia; Allison Tam; Richard Webster; Susan Brammah; Francesca Filippini; John Pollard; Judy Spies; Andre E. Minoche; Mark J. Cowley; Sarah Risen; Nina N. Powell-Hamilton; Jessica E. Tusi; LaDonna Immken; Honey Nagakura; Christine Bole-Feysot; Patrick Nitschké; Alexandrine Garrigue; Geneviève de Saint Basile; Emma Kivuva; Richard H. Scott; Augusto Rendon; Arnold Munnich; William Newman; Bronwyn Kerr; Claude Besmond; Jill A. Rosenfeld; Jeanne Amiel; Michael Field; Jozef Gecz
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Elizabeth E. Palmer, Raman Kumar, Christopher T. Gordon, Marie Shaw, Laurence Hubert, Renee Carroll, Marlène Rio, Lucinda Murray, Melanie Leffler, Tracy Dudding-Byth, Myriam Oufadem, Seema R. Lalani, Andrea M. Lewis, Fan Xia, Allison Tam, Richard Webster, Susan Brammah, Francesca Filippini, John Pollard, Judy Spies, Andre E. Minoche, Mark J. Cowley, Sarah Risen, Nina N. Powell-Hamilton, Jessica E. Tusi, LaDonna Immken, Honey Nagakura, Christine Bole-Feysot, Patrick Nitschké, Alexandrine Garrigue, Geneviève de Saint Basile, Emma Kivuva, Richard H. Scott, Augusto Rendon, Arnold Munnich, William Newman, Bronwyn Kerr, Claude Besmond, Jill A. Rosenfeld, Jeanne Amiel, Michael Field, Jozef Gecz
      A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.009
  • DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation
    • Authors: Melissa A. Richard; Tianxiao Huan; Symen Ligthart; Rahul Gondalia; Min A. Jhun; Jennifer A. Brody; Marguerite R. Irvin; Riccardo Marioni; Jincheng Shen; Pei-Chien Tsai; May E. Montasser; Yucheng Jia; Catriona Syme; Elias L. Salfati; Eric Boerwinkle; Weihua Guan; Thomas H. Mosley; Jan Bressler; Alanna C. Morrison; Chunyu Liu; Michael M. Mendelson; André G. Uitterlinden; Joyce B. van Meurs; Oscar H. Franco; Guosheng Zhang; Yun Li; James D. Stewart; Joshua C. Bis; Bruce M. Psaty; Yii-Der Ida Chen; Sharon L.R. Kardia; Wei Zhao; Stephen T. Turner; Devin Absher; Stella Aslibekyan; John M. Starr; Allan F. McRae; Lifang Hou; Allan C. Just; Joel D. Schwartz; Pantel S. Vokonas; Cristina Menni; Tim D. Spector; Alan Shuldiner; Coleen M. Damcott; Jerome I. Rotter; Walter Palmas; Yongmei Liu; Tomáš Paus; Steve Horvath; Jeffrey R. O’Connell; Xiuqing Guo; Zdenka Pausova; Themistocles L. Assimes; Nona Sotoodehnia; Jennifer A. Smith; Donna K. Arnett; Ian J. Deary; Andrea A. Baccarelli; Jordana T. Bell; Eric Whitsel; Abbas Dehghan; Daniel Levy; Myriam Fornage; Bastiaan T. Heijmans; Peter A.C. ’t Hoen; Joyce van Meurs; Aaron Isaacs; Rick Jansen; Lude Franke; Dorret I. Boomsma; René Pool; Jenny van Dongen; Jouke J. Hottenga; Marleen M.J. van Greevenbroek; Coen D.A. Stehouwer; Carla J.H. van der Kallen; Casper G. Schalkwijk; Cisca Wijmenga; Alexandra Zhernakova; Ettje F. Tigchelaar; P. Eline Slagboom; Marian Beekman; Joris Deelen; Diana van Heemst; Jan H. Veldink; Leonard H. van den Berg; Cornelia M. van Duijn; Albert Hofman; André G. Uitterlinden; P. Mila Jhamai; Michael Verbiest; H. Eka D. Suchiman; Marijn Verkerk; Ruud van der Breggen; Jeroen van Rooij; Nico Lakenberg; Hailiang Mei; Maarten van Iterson; Michiel van Galen; Jan Bot; Peter van ’t Hof; Patrick Deelen; Irene Nooren; Matthijs Moed; Martijn Vermaat; Dasha V. Zhernakova; René Luijk; Marc Jan Bonder; Freerk van Dijk; Wibowo Arindrarto; Szymon M. Kielbasa; Morris A. Swertz; Erik W. van Zwet
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Melissa A. Richard, Tianxiao Huan, Symen Ligthart, Rahul Gondalia, Min A. Jhun, Jennifer A. Brody, Marguerite R. Irvin, Riccardo Marioni, Jincheng Shen, Pei-Chien Tsai, May E. Montasser, Yucheng Jia, Catriona Syme, Elias L. Salfati, Eric Boerwinkle, Weihua Guan, Thomas H. Mosley, Jan Bressler, Alanna C. Morrison, Chunyu Liu, Michael M. Mendelson, André G. Uitterlinden, Joyce B. van Meurs, Oscar H. Franco, Guosheng Zhang, Yun Li, James D. Stewart, Joshua C. Bis, Bruce M. Psaty, Yii-Der Ida Chen, Sharon L.R. Kardia, Wei Zhao, Stephen T. Turner, Devin Absher, Stella Aslibekyan, John M. Starr, Allan F. McRae, Lifang Hou, Allan C. Just, Joel D. Schwartz, Pantel S. Vokonas, Cristina Menni, Tim D. Spector, Alan Shuldiner, Coleen M. Damcott, Jerome I. Rotter, Walter Palmas, Yongmei Liu, Tomáš Paus, Steve Horvath, Jeffrey R. O’Connell, Xiuqing Guo, Zdenka Pausova, Themistocles L. Assimes, Nona Sotoodehnia, Jennifer A. Smith, Donna K. Arnett, Ian J. Deary, Andrea A. Baccarelli, Jordana T. Bell, Eric Whitsel, Abbas Dehghan, Daniel Levy, Myriam Fornage
      Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10−7; replication: N = 7,182, p < 1.6 × 10−3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.09.028
  • Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment
    • Authors: John R. Shaffer; Jinxi Li; Myoung Keun Lee; Jasmien Roosenboom; Ekaterina Orlova; Kaustabh Adhikari; Carla Gallo; Giovanni Poletti; Lavinia Schuler-Faccini; Maria-Cátira Bortolini; Samuel Canizales-Quinteros; Francisco Rothhammer; Gabriel Bedoya; Rolando González-José; Paige E. Pfeffer; Christopher A. Wollenschlaeger; Jacqueline T. Hecht; George L. Wehby; Lina M. Moreno; Anan Ding; Li Jin; Yajun Yang; Jenna C. Carlson; Elizabeth J. Leslie; Eleanor Feingold; Mary L. Marazita; David A. Hinds; Timothy C. Cox; Sijia Wang; Andrés Ruiz-Linares; Seth M. Weinberg; Michelle Agee; Babak Alipanahi; Adam Auton; Robert K. Bell; Katarzyna Bryc; Sarah L. Elson; Pierre Fontanillas; Nicholas A. Furlotte; David A. Hinds; Bethann S. Hromatka; Karen E. Huber; Aaron Kleinman; Nadia K. Litterman; Matthew H. McIntyre; Joanna L. Mountain; Elizabeth S. Noblin; Carrie A.M. Northover; Steven J. Pitts; J. Fah Sathirapongsasuti; Olga V. Sazonova; Janie F. Shelton; Suyash Shringarpure; Chao Tian; Joyce Y. Tung; Vladimir Vacic; Catherine H. Wilson
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): John R. Shaffer, Jinxi Li, Myoung Keun Lee, Jasmien Roosenboom, Ekaterina Orlova, Kaustabh Adhikari, Carla Gallo, Giovanni Poletti, Lavinia Schuler-Faccini, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Francisco Rothhammer, Gabriel Bedoya, Rolando González-José, Paige E. Pfeffer, Christopher A. Wollenschlaeger, Jacqueline T. Hecht, George L. Wehby, Lina M. Moreno, Anan Ding, Li Jin, Yajun Yang, Jenna C. Carlson, Elizabeth J. Leslie, Eleanor Feingold, Mary L. Marazita, David A. Hinds, Timothy C. Cox, Sijia Wang, Andrés Ruiz-Linares, Seth M. Weinberg
      The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10−8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.001
  • Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause
           Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12
    • Authors: Tiong Yang Tan; Claudia Gonzaga-Jauregui; Elizabeth J. Bhoj; Kevin A. Strauss; Karlla Brigatti; Erik Puffenberger; Dong Li; LiQin Xie; Nanditha Das; Ioanna Skubas; Ron A. Deckelbaum; Virginia Hughes; Susannah Brydges; Sarah Hatsell; Chia-Jen Siao; Melissa G. Dominguez; Aris Economides; John D. Overton; Valerie Mayne; Peter J. Simm; Bryn O. Jones; Stefanie Eggers; Gwenaël Le Guyader; Fanny Pelluard; Tobias B. Haack; Marc Sturm; Angelika Riess; Stephan Waldmueller; Michael Hofbeck; Katharina Steindl; Pascal Joset; Anita Rauch; Hakon Hakonarson; Naomi L. Baker; Peter G. Farlie
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Tiong Yang Tan, Claudia Gonzaga-Jauregui, Elizabeth J. Bhoj, Kevin A. Strauss, Karlla Brigatti, Erik Puffenberger, Dong Li, LiQin Xie, Nanditha Das, Ioanna Skubas, Ron A. Deckelbaum, Virginia Hughes, Susannah Brydges, Sarah Hatsell, Chia-Jen Siao, Melissa G. Dominguez, Aris Economides, John D. Overton, Valerie Mayne, Peter J. Simm, Bryn O. Jones, Stefanie Eggers, Gwenaël Le Guyader, Fanny Pelluard, Tobias B. Haack, Marc Sturm, Angelika Riess, Stephan Waldmueller, Michael Hofbeck, Katharina Steindl, Pascal Joset, Anita Rauch, Hakon Hakonarson, Naomi L. Baker, Peter G. Farlie
      Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.006
  • The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and
           Post-admixture Selection in the Makranis of Pakistan
    • Authors: Romuald Laso-Jadart; Christine Harmant; Hélène Quach; Nora Zidane; Chris Tyler-Smith; Qasim Mehdi; Qasim Ayub; Lluis Quintana-Murci; Etienne Patin
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Romuald Laso-Jadart, Christine Harmant, Hélène Quach, Nora Zidane, Chris Tyler-Smith, Qasim Mehdi, Qasim Ayub, Lluis Quintana-Murci, Etienne Patin
      From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to ∼300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of homozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group—believed to confer resistance against Plasmodium vivax infection—was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria-endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations.

      PubDate: 2017-11-11T11:09:35Z
      DOI: 10.1016/j.ajhg.2017.09.025
  • Functional Consequences of CHRNA7 Copy-Number Alterations in Induced
           Pluripotent Stem Cells and Neural Progenitor Cells
    • Authors: Madelyn A. Gillentine; Jiani Yin; Aleksandar Bajic; Ping Zhang; Steven Cummock; Jean J. Kim; Christian P. Schaaf
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Madelyn A. Gillentine, Jiani Yin, Aleksandar Bajic, Ping Zhang, Steven Cummock, Jean J. Kim, Christian P. Schaaf
      Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs. Unexpectedly, both deletions and duplications lead to decreased α7 nAChR-associated calcium flux. For deletions, this decrease in α7 nAChR-dependent calcium flux is expected due to haploinsufficiency of CHRNA7. For duplications, we found that increased expression of CHRNA7 mRNA is associated with higher expression of nAChR-specific and resident ER chaperones, indicating increased ER stress. This is likely a consequence of inefficient chaperoning and accumulation of α7 subunits in the ER, as opposed to being incorporated into functional α7 nAChRs at the cell membrane. Here, we showed that α7 nAChR-dependent calcium signal cascades are downregulated in both 15q13.3 deletion and duplication NPCs. While it may seem surprising that genomic changes in opposite direction have consequences on downstream pathways that are in similar direction, it aligns with clinical data, which suggest that both individuals with deletions and duplications of 15q13.3 manifest neuropsychiatric disease and cognitive deficits.

      PubDate: 2017-11-11T11:09:35Z
      DOI: 10.1016/j.ajhg.2017.09.024
  • A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin
           Architecture and Gene Expression
    • Authors: Michael Gallagher; Marijan Posavi Peng Huang Travis Unger Yosef Berlyand
      Abstract: Publication date: Available online 19 October 2017
      Source:The American Journal of Human Genetics
      Author(s): Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, Alice S. Chen-Plotkin
      Neurodegenerative diseases pose an extraordinary threat to the world’s aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.

      PubDate: 2017-10-29T09:27:30Z
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Heriot-Watt University
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