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Showing 1 - 200 of 3043 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 22, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 21, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 84, 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: 352, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, 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   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 235, 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: 23, 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: 4)
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: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, 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: 25, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, 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: 25, 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: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
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: 11)
Advances in Digestive Medicine     Open Access   (Followers: 6)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 41, 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: 50, 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: 15, 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 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: 35, 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 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: 9)
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: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, 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: 3)
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: 15, 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: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 61)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, 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 Research     Full-text available via subscription   (Followers: 353, 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: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, 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: 325, 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: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 406, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 39, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, 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  
Algal Research     Partially Free   (Followers: 8, 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: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 39, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 8, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, 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: 233, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 58, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5)
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: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 22, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, 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: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 57, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 11)
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: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 167, 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: 11)
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: 161, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 1, SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Human Genetics
  [SJR: 8.769]   [H-I: 256]   [31 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3043 journals]
  • Variant Interpretation: Functional Assays to the Rescue
    • Authors: Lea M. Starita; Nadav Ahituv; Maitreya J. Dunham; Jacob O. Kitzman; Frederick P. Roth; Georg Seelig; Jay Shendure; Douglas M. Fowler
      Pages: 315 - 325
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Lea M. Starita, Nadav Ahituv, Maitreya J. Dunham, Jacob O. Kitzman, Frederick P. Roth, Georg Seelig, Jay Shendure, Douglas M. Fowler
      Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant’s functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of “lookup tables” of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.07.014
  • CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine
           Malformations, and Developmental Delays
    • Authors: Christian Windpassinger; Juliette Piard; Carine Bonnard; Majid Alfadhel; Shuhui Lim; Xavier Bisteau; Stéphane Blouin; Nur’Ain B. Ali; Alvin Yu Jin Ng; Hao Lu; Sumanty Tohari; S. Zakiah A. Talib; Noémi van Hul; Matias J. Caldez; Lionel Van Maldergem; Gökhan Yigit; Hülya Kayserili; Sameh A. Youssef; Vincenzo Coppola; Alain de Bruin; Lino Tessarollo; Hyungwon Choi; Verena Rupp; Katharina Roetzer; Paul Roschger; Klaus Klaushofer; Janine Altmüller; Sudipto Roy; Byrappa Venkatesh; Rudolf Ganger; Franz Grill; Farid Ben Chehida; Bernd Wollnik; Umut Altunoglu; Ali Al Kaissi; Bruno Reversade; Philipp Kaldis
      Pages: 391 - 403
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Christian Windpassinger, Juliette Piard, Carine Bonnard, Majid Alfadhel, Shuhui Lim, Xavier Bisteau, Stéphane Blouin, Nur’Ain B. Ali, Alvin Yu Jin Ng, Hao Lu, Sumanty Tohari, S. Zakiah A. Talib, Noémi van Hul, Matias J. Caldez, Lionel Van Maldergem, Gökhan Yigit, Hülya Kayserili, Sameh A. Youssef, Vincenzo Coppola, Alain de Bruin, Lino Tessarollo, Hyungwon Choi, Verena Rupp, Katharina Roetzer, Paul Roschger, Klaus Klaushofer, Janine Altmüller, Sudipto Roy, Byrappa Venkatesh, Rudolf Ganger, Franz Grill, Farid Ben Chehida, Bernd Wollnik, Umut Altunoglu, Ali Al Kaissi, Bruno Reversade, Philipp Kaldis
      In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease’s effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.08.003
  • A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional
           Variants Implicated in Fibrosis
    • Authors: Michael Ng; Dipti Thakkar; Lorraine Southam; Paul Werker; Roel Ophoff; Kerstin Becker; Michael Nothnagel; Andre Franke; Peter Nürnberg; Ana Isabel Espirito-Santo; David Izadi; Hans Christian Hennies; Jagdeep Nanchahal; Eleftheria Zeggini; Dominic Furniss
      Pages: 417 - 427
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Michael Ng, Dipti Thakkar, Lorraine Southam, Paul Werker, Roel Ophoff, Kerstin Becker, Michael Nothnagel, Andre Franke, Peter Nürnberg, Ana Isabel Espirito-Santo, David Izadi, Hans Christian Hennies, Jagdeep Nanchahal, Eleftheria Zeggini, Dominic Furniss
      Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10−8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.08.006
  • Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
    • Authors: Lauren M. Watson; Elizabeth Bamber; Ricardo Parolin Schnekenberg; Jonathan Williams; Conceição Bettencourt; Jennifer Lickiss; Katherine Fawcett; Samuel Clokie; Yvonne Wallis; Penny Clouston; David Sims; Henry Houlden; Esther B.E. Becker; Andrea H. Németh
      Pages: 451 - 458
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Lauren M. Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B.E. Becker, Andrea H. Németh
      The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.08.005
  • A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and
           Female Infertility
    • Authors: Tailai Chen; Yuehong Bian; Xiaoman Liu; Shigang Zhao; Keliang Wu; Lei Yan; Mei Li; Zhenglin Yang; Hongbin Liu; Han Zhao; Zi-Jiang Chen
      Pages: 459 - 465
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang Wu, Lei Yan, Mei Li, Zhenglin Yang, Hongbin Liu, Han Zhao, Zi-Jiang Chen
      Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.08.001
  • RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
    • Authors: Margot R.F. Reijnders; Nurhuda M. Ansor; Maria Kousi; Wyatt W. Yue; Perciliz L. Tan; Katie Clarkson; Jill Clayton-Smith; Ken Corning; Julie R. Jones; Wayne W.K. Lam; Grazia M.S. Mancini; Carlo Marcelis; Shehla Mohammed; Rolph Pfundt; Maian Roifman; Ronald Cohn; David Chitayat; Tom H. Millard; Nicholas Katsanis; Han G. Brunner; Siddharth Banka
      Pages: 466 - 477
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Margot R.F. Reijnders, Nurhuda M. Ansor, Maria Kousi, Wyatt W. Yue, Perciliz L. Tan, Katie Clarkson, Jill Clayton-Smith, Ken Corning, Julie R. Jones, Wayne W.K. Lam, Grazia M.S. Mancini, Carlo Marcelis, Shehla Mohammed, Rolph Pfundt, Maian Roifman, Ronald Cohn, David Chitayat, Tom H. Millard, Nicholas Katsanis, Han G. Brunner, Siddharth Banka
      RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.08.007
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 159 - 160
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.008
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 161 - 162
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kathryn B. Garber

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.009
  • William J. “Jack” Schull (1922–2017): Gentleman,
    • Authors: Kenneth M. Weiss
      Pages: 163 - 166
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kenneth M. Weiss

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.003
  • Human Germline Genome Editing
    • Authors: Kelly E. Ormond; Douglas P. Mortlock; Derek T. Scholes; Yvonne Bombard; Lawrence C. Brody; W. Andrew Faucett; Nanibaa’ A. Garrison; Laura Hercher; Rosario Isasi; Anna Middleton; Kiran Musunuru; Daniel Shriner; Alice Virani; Caroline E. Young
      Pages: 167 - 176
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kelly E. Ormond, Douglas P. Mortlock, Derek T. Scholes, Yvonne Bombard, Lawrence C. Brody, W. Andrew Faucett, Nanibaa’ A. Garrison, Laura Hercher, Rosario Isasi, Anna Middleton, Kiran Musunuru, Daniel Shriner, Alice Virani, Caroline E. Young
      With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors. These groups, as well as the American Society for Reproductive Medicine, Asia Pacific Society of Human Genetics, British Society for Genetic Medicine, Human Genetics Society of Australasia, Professional Society of Genetic Counselors in Asia, and Southern African Society for Human Genetics, endorsed the final statement. The statement includes the following positions. (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.012
  • From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics
           of Health
    • Authors: Jesse D. Riordan; Joseph H. Nadeau
      Pages: 177 - 191
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Jesse D. Riordan, Joseph H. Nadeau
      Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called “modifier genes” that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.004
  • Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative
           Traits in Minority Populations
    • Authors: Marc A. Coram; Huaying Fang; Sophie I. Candille; Themistocles L. Assimes; Hua Tang
      Pages: 218 - 226
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Marc A. Coram, Huaying Fang, Sophie I. Candille, Themistocles L. Assimes, Hua Tang
      An essential component of precision medicine is the ability to predict an individual’s risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.015
  • Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on
           Vitamin D Levels and Risk of Multiple Sclerosis
    • Authors: Despoina Manousaki; Tom Dudding; Simon Haworth; Yi-Hsiang Hsu; Ching-Ti Liu; Carolina Medina-Gómez; Trudy Voortman; Nathalie van der Velde; Håkan Melhus; Cassianne Robinson-Cohen; Diana L. Cousminer; Maria Nethander; Liesbeth Vandenput; Raymond Noordam; Vincenzo Forgetta; Celia M.T. Greenwood; Mary L. Biggs; Bruce M. Psaty; Jerome I. Rotter; Babette S. Zemel; Jonathan A. Mitchell; Bruce Taylor; Mattias Lorentzon; Magnus Karlsson; Vincent V.W. Jaddoe; Henning Tiemeier; Natalia Campos-Obando; Oscar H. Franco; Andre G. Utterlinden; Linda Broer; Natasja M. van Schoor; Annelies C. Ham; M. Arfan Ikram; David Karasik; Renée de Mutsert; Frits R. Rosendaal; Martin den Heijer; Thomas J. Wang; Lars Lind; Eric S. Orwoll; Dennis O. Mook-Kanamori; Karl Michaëlsson; Bryan Kestenbaum; Claes Ohlsson; Dan Mellström; Lisette C.P.G.M. de Groot; Struan F.A. Grant; Douglas P. Kiel; M. Carola Zillikens; Fernando Rivadeneira; Stephen Sawcer; Nicholas J. Timpson; J. Brent Richards
      Pages: 227 - 238
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Despoina Manousaki, Tom Dudding, Simon Haworth, Yi-Hsiang Hsu, Ching-Ti Liu, Carolina Medina-Gómez, Trudy Voortman, Nathalie van der Velde, Håkan Melhus, Cassianne Robinson-Cohen, Diana L. Cousminer, Maria Nethander, Liesbeth Vandenput, Raymond Noordam, Vincenzo Forgetta, Celia M.T. Greenwood, Mary L. Biggs, Bruce M. Psaty, Jerome I. Rotter, Babette S. Zemel, Jonathan A. Mitchell, Bruce Taylor, Mattias Lorentzon, Magnus Karlsson, Vincent V.W. Jaddoe, Henning Tiemeier, Natalia Campos-Obando, Oscar H. Franco, Andre G. Utterlinden, Linda Broer, Natasja M. van Schoor, Annelies C. Ham, M. Arfan Ikram, David Karasik, Renée de Mutsert, Frits R. Rosendaal, Martin den Heijer, Thomas J. Wang, Lars Lind, Eric S. Orwoll, Dennis O. Mook-Kanamori, Karl Michaëlsson, Bryan Kestenbaum, Claes Ohlsson, Dan Mellström, Lisette C.P.G.M. de Groot, Struan F.A. Grant, Douglas P. Kiel, M. Carola Zillikens, Fernando Rivadeneira, Stephen Sawcer, Nicholas J. Timpson, J. Brent Richards
      Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78–2.78, p = 1.26 × 10−12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.014
  • Biallelic Mutations in MRPS34 Lead to Instability of the Small
           Mitoribosomal Subunit and Leigh Syndrome
    • Authors: Nicole J. Lake; Bryn D. Webb; David A. Stroud; Tara R. Richman; Benedetta Ruzzenente; Alison G. Compton; Hayley S. Mountford; Juliette Pulman; Coralie Zangarelli; Marlene Rio; Nathalie Bodaert; Zahra Assouline; Mingma D. Sherpa; Eric E. Schadt; Sander M. Houten; James Byrnes; Elizabeth M. McCormick; Zarazuela Zolkipli-Cunningham; Katrina Haude; Zhancheng Zhang; Kyle Retterer; Renkui Bai; Sarah E. Calvo; Vamsi K. Mootha; John Christodoulou; Agnes Rötig; Aleksandra Filipovska; Ingrid Cristian; Marni J. Falk; Metodi D. Metodiev; David R. Thorburn
      Pages: 239 - 254
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Nicole J. Lake, Bryn D. Webb, David A. Stroud, Tara R. Richman, Benedetta Ruzzenente, Alison G. Compton, Hayley S. Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Bodaert, Zahra Assouline, Mingma D. Sherpa, Eric E. Schadt, Sander M. Houten, James Byrnes, Elizabeth M. McCormick, Zarazuela Zolkipli-Cunningham, Katrina Haude, Zhancheng Zhang, Kyle Retterer, Renkui Bai, Sarah E. Calvo, Vamsi K. Mootha, John Christodoulou, Agnes Rötig, Aleksandra Filipovska, Ingrid Cristian, Marni J. Falk, Metodi D. Metodiev, David R. Thorburn
      The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322−10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.005
  • Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13
           by Modulating the Response to DNA Damage
    • Authors: Joshua A. Betts; Mahdi Moradi Marjaneh; Fares Al-Ejeh; Yi Chieh Lim; Wei Shi; Haran Sivakumaran; Romain Tropée; Ann-Marie Patch; Michael B. Clark; Nenad Bartonicek; Adrian P. Wiegmans; Kristine M. Hillman; Susanne Kaufmann; Amanda L. Bain; Brian S. Gloss; Joanna Crawford; Stephen Kazakoff; Shivangi Wani; Shu W. Wen; Bryan Day; Andreas Möller; Nicole Cloonan; John Pearson; Melissa A. Brown; Timothy R. Mercer; Nicola Waddell; Kum Kum Khanna; Eloise Dray; Marcel E. Dinger; Stacey L. Edwards; Juliet D. French
      Pages: 255 - 266
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Joshua A. Betts, Mahdi Moradi Marjaneh, Fares Al-Ejeh, Yi Chieh Lim, Wei Shi, Haran Sivakumaran, Romain Tropée, Ann-Marie Patch, Michael B. Clark, Nenad Bartonicek, Adrian P. Wiegmans, Kristine M. Hillman, Susanne Kaufmann, Amanda L. Bain, Brian S. Gloss, Joanna Crawford, Stephen Kazakoff, Shivangi Wani, Shu W. Wen, Bryan Day, Andreas Möller, Nicole Cloonan, John Pearson, Melissa A. Brown, Timothy R. Mercer, Nicola Waddell, Kum Kum Khanna, Eloise Dray, Marcel E. Dinger, Stacey L. Edwards, Juliet D. French
      Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.007
  • Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with
           Neurodegeneration in Childhood
    • Authors: Simon Edvardson; Claudia M. Nicolae; Pankaj B. Agrawal; Cyril Mignot; Katelyn Payne; Asuri Narayan Prasad; Chitra Prasad; Laurie Sadler; Caroline Nava; Thomas E. Mullen; Amber Begtrup; Berivan Baskin; Zöe Powis; Avraham Shaag; Boris Keren; George-Lucian Moldovan; Orly Elpeleg
      Pages: 267 - 273
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Simon Edvardson, Claudia M. Nicolae, Pankaj B. Agrawal, Cyril Mignot, Katelyn Payne, Asuri Narayan Prasad, Chitra Prasad, Laurie Sadler, Caroline Nava, Thomas E. Mullen, Amber Begtrup, Berivan Baskin, Zöe Powis, Avraham Shaag, Boris Keren, George-Lucian Moldovan, Orly Elpeleg
      Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5–7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5′- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.002
  • Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect
           Associated with Severe Neonatal Encephalopathy
    • Authors: Florence Habarou; Yamina Hamel; Tobias B. Haack; René G. Feichtinger; Elise Lebigot; Iris Marquardt; Kanetee Busiah; Cécile Laroche; Marine Madrange; Coraline Grisel; Clément Pontoizeau; Monika Eisermann; Audrey Boutron; Dominique Chrétien; Bernadette Chadefaux-Vekemans; Robert Barouki; Christine Bole-Feysot; Patrick Nitschke; Nicolas Goudin; Nathalie Boddaert; Ivan Nemazanyy; Agnès Delahodde; Stefan Kölker; Richard J. Rodenburg; G. Christoph Korenke; Thomas Meitinger; Tim M. Strom; Holger Prokisch; Agnes Rotig; Chris Ottolenghi; Johannes A. Mayr; Pascale de Lonlay
      Pages: 283 - 290
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Florence Habarou, Yamina Hamel, Tobias B. Haack, René G. Feichtinger, Elise Lebigot, Iris Marquardt, Kanetee Busiah, Cécile Laroche, Marine Madrange, Coraline Grisel, Clément Pontoizeau, Monika Eisermann, Audrey Boutron, Dominique Chrétien, Bernadette Chadefaux-Vekemans, Robert Barouki, Christine Bole-Feysot, Patrick Nitschke, Nicolas Goudin, Nathalie Boddaert, Ivan Nemazanyy, Agnès Delahodde, Stefan Kölker, Richard J. Rodenburg, G. Christoph Korenke, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Agnes Rotig, Chris Ottolenghi, Johannes A. Mayr, Pascale de Lonlay
      Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals’ fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.001
  • Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and
           Golgi Dysfunction
    • Authors: Miroslav P. Milev; Megan E. Grout; Djenann Saint-Dic; Yong-Han Hank Cheng; Ian A. Glass; Christopher J. Hale; David S. Hanna; Michael O. Dorschner; Keshika Prematilake; Avraham Shaag; Orly Elpeleg; Michael Sacher; Dan Doherty; Simon Edvardson
      Pages: 291 - 299
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Miroslav P. Milev, Megan E. Grout, Djenann Saint-Dic, Yong-Han Hank Cheng, Ian A. Glass, Christopher J. Hale, David S. Hanna, Michael O. Dorschner, Keshika Prematilake, Avraham Shaag, Orly Elpeleg, Michael Sacher, Dan Doherty, Simon Edvardson
      Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs∗14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs∗7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.006
  • De Novo Mutations in YWHAG Cause Early-Onset Epilepsy
    • Authors: Ilaria Guella; Marna B. McKenzie; Daniel M. Evans; Sarah E. Buerki; Eric B. Toyota; Margot I. Van Allen; Mohnish Suri; Frances Elmslie; Marleen E.H. Simon; Koen L.I. van Gassen; Delphine Héron; Boris Keren; Caroline Nava; Mary B. Connolly; Michelle Demos; Matthew J. Farrer; Shelin Adam; Cyrus Boelman; Corneliu Bolbocean; Tara Candido; Patrice Eydoux; Gabriella Horvath; Linda Huh; Tanya N. Nelson; Graham Sinclair; Clara van Karnebeek; Suzanne Vercauteren
      Pages: 300 - 310
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Ilaria Guella, Marna B. McKenzie, Daniel M. Evans, Sarah E. Buerki, Eric B. Toyota, Margot I. Van Allen, Mohnish Suri, Frances Elmslie, Marleen E.H. Simon, Koen L.I. van Gassen, Delphine Héron, Boris Keren, Caroline Nava, Mary B. Connolly, Michelle Demos, Matthew J. Farrer
      Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder’s etiology and genotype-phenotype correlations.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.004
  • 10 Years of GWAS Discovery: Biology, Function, and Translation
    • Authors: Peter M. Visscher; Naomi R. Wray; Qian Zhang; Pamela Sklar; Mark I. McCarthy; Matthew A. Brown; Jian Yang
      Pages: 5 - 22
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Peter M. Visscher, Naomi R. Wray, Qian Zhang, Pamela Sklar, Mark I. McCarthy, Matthew A. Brown, Jian Yang
      Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.005
  • Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms
           of Autoimmune Disease
    • Authors: Parisa Shooshtari; Hailiang Huang; Chris Cotsapas
      Pages: 75 - 86
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Parisa Shooshtari, Hailiang Huang, Chris Cotsapas
      Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.06.001
  • A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1,
           Mapping to SCA37, Causes Spinocerebellar Ataxia
    • Authors: Ana I. Seixas; Joana R. Loureiro; Cristina Costa; Andrés Ordóñez-Ugalde; Hugo Marcelino; Cláudia L. Oliveira; José L. Loureiro; Ashutosh Dhingra; Eva Brandão; Vitor T. Cruz; Angela Timóteo; Beatriz Quintáns; Guy A. Rouleau; Patrizia Rizzu; Ángel Carracedo; José Bessa; Peter Heutink; Jorge Sequeiros; Maria J. Sobrido; Paula Coutinho; Isabel Silveira
      Pages: 87 - 103
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Ana I. Seixas, Joana R. Loureiro, Cristina Costa, Andrés Ordóñez-Ugalde, Hugo Marcelino, Cláudia L. Oliveira, José L. Loureiro, Ashutosh Dhingra, Eva Brandão, Vitor T. Cruz, Angela Timóteo, Beatriz Quintáns, Guy A. Rouleau, Patrizia Rizzu, Ángel Carracedo, José Bessa, Peter Heutink, Jorge Sequeiros, Maria J. Sobrido, Paula Coutinho, Isabel Silveira
      Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7–400] and [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5′ UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.06.007
  • A Fast Association Test for Identifying Pathogenic Variants Involved in
           Rare Diseases
    • Authors: Daniel Greene; Sylvia Richardson; Ernest Turro
      Pages: 104 - 114
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Daniel Greene, Sylvia Richardson, Ernest Turro
      We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.05.015
  • SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant
           Association Studies Using Whole-Genome and Exome Sequence Data
    • Authors: Di Zhang; Linhai Zhao; Biao Li; Zongxiao He; Gao T. Wang; Dajiang J. Liu; Suzanne M. Leal
      Pages: 115 - 122
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Di Zhang, Linhai Zhao, Biao Li, Zongxiao He, Gao T. Wang, Dajiang J. Liu, Suzanne M. Leal
      Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed and efficiency of performing data quality control, annotation, and association analysis. To demonstrate the versatility and speed of SEQSpark, we analyzed whole-genome sequence data from the UK10K, testing for associations with waist-to-hip ratios. The analysis, which was completed in 1.5 hr, included loading data, annotation, principal component analysis, and single variant and rare variant aggregate association analysis of >9 million variants. For rare variant aggregate analysis, an exome-wide significant association (p < 2.5 × 10−6) was observed with CCDC62 (SKAT-O [p = 6.89 × 10−7], combined multivariate collapsing [p = 1.48 × 10−6], and burden of rare variants [p = 1.48 × 10−6]). SEQSpark was also used to analyze 50,000 simulated exomes and it required 1.75 hr for the analysis of a quantitative trait using several rare variant aggregate association methods. Additionally, the performance of SEQSpark was compared to Variant Association Tools and PLINK/SEQ. SEQSpark was always faster and in some situations computation was reduced to a hundredth of the time. SEQSpark will empower large sequence-based epidemiological studies to quickly elucidate genetic variation involved in the etiology of complex traits.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.05.017
  • Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon
           Intestinal Hypoperistalsis Syndrome
    • Authors: Danny Halim; Erwin Brosens; Françoise Muller; Michael F. Wangler; Arthur L. Beaudet; James R. Lupski; Zeynep H. Coban Akdemir; Michael Doukas; Hans J. Stoop; Bianca M. de Graaf; Rutger W.W. Brouwer; Wilfred F.J. van Ijcken; Jean-François Oury; Jonathan Rosenblatt; Alan J. Burns; Dick Tibboel; Robert M.W. Hofstra; Maria M. Alves
      Pages: 123 - 129
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Danny Halim, Erwin Brosens, Françoise Muller, Michael F. Wangler, Arthur L. Beaudet, James R. Lupski, Zeynep H. Coban Akdemir, Michael Doukas, Hans J. Stoop, Bianca M. de Graaf, Rutger W.W. Brouwer, Wilfred F.J. van Ijcken, Jean-François Oury, Jonathan Rosenblatt, Alan J. Burns, Dick Tibboel, Robert M.W. Hofstra, Maria M. Alves
      Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs∗51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.05.011
  • A Genetic Variant Ameliorates β-Thalassemia Severity by
           Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression
    • Authors: Diyu Chen; Yangjin Zuo; Xinhua Zhang; Yuhua Ye; Xiuqin Bao; Haiyan Huang; Wanicha Tepakhan; Lijuan Wang; Junyi Ju; Guangfu Chen; Mincui Zheng; Dun Liu; Shuodan Huang; Lu Zong; Changgang Li; Yajun Chen; Chenguang Zheng; Lihong Shi; Quan Zhao; Qiang Wu; Supan Fucharoen; Cunyou Zhao; Xiangmin Xu
      Pages: 130 - 138
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Diyu Chen, Yangjin Zuo, Xinhua Zhang, Yuhua Ye, Xiuqin Bao, Haiyan Huang, Wanicha Tepakhan, Lijuan Wang, Junyi Ju, Guangfu Chen, Mincui Zheng, Dun Liu, Shuodan Huang, Lu Zong, Changgang Li, Yajun Chen, Chenguang Zheng, Lihong Shi, Quan Zhao, Qiang Wu, Supan Fucharoen, Cunyou Zhao, Xiangmin Xu
      A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal Aγ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.05.012
  • WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual
           Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
    • Authors: Cara M. Skraban; Constance F. Wells; Preetha Markose; Megan T. Cho; Addie I. Nesbitt; P.Y. Billie Au; Amber Begtrup; John A. Bernat; Lynne M. Bird; Kajia Cao; Arjan P.M. de Brouwer; Elizabeth H. Denenberg; Ganka Douglas; Kristin M. Gibson; Katheryn Grand; Alice Goldenberg; A. Micheil Innes; Jane Juusola; Marlies Kempers; Esther Kinning; David M. Markie; Martina M. Owens; Katelyn Payne; Richard Person; Rolph Pfundt; Amber Stocco; Claire L.S. Turner; Nienke E. Verbeek; Laurence E. Walsh; Taylor C. Warner; Patricia G. Wheeler; Dagmar Wieczorek; Alisha B. Wilkens; Evelien Zonneveld-Huijssoon; Tjitske Kleefstra; Stephen P. Robertson; Avni Santani; Koen L.I. van Gassen; Matthew A. Deardorff
      Pages: 139 - 148
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Cara M. Skraban, Constance F. Wells, Preetha Markose, Megan T. Cho, Addie I. Nesbitt, P.Y. Billie Au, Amber Begtrup, John A. Bernat, Lynne M. Bird, Kajia Cao, Arjan P.M. de Brouwer, Elizabeth H. Denenberg, Ganka Douglas, Kristin M. Gibson, Katheryn Grand, Alice Goldenberg, A. Micheil Innes, Jane Juusola, Marlies Kempers, Esther Kinning, David M. Markie, Martina M. Owens, Katelyn Payne, Richard Person, Rolph Pfundt, Amber Stocco, Claire L.S. Turner, Nienke E. Verbeek, Laurence E. Walsh, Taylor C. Warner, Patricia G. Wheeler, Dagmar Wieczorek, Alisha B. Wilkens, Evelien Zonneveld-Huijssoon, Tjitske Kleefstra, Stephen P. Robertson, Avni Santani, Koen L.I. van Gassen, Matthew A. Deardorff
      We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.06.002
  • REST Final-Exon-Truncating Mutations Cause Hereditary Gingival
    • Authors: Yavuz Bayram; Janson J. White; Nursel Elcioglu; Megan T. Cho; Neda Zadeh; Asuman Gedikbasi; Sukru Palanduz; Sukru Ozturk; Kivanc Cefle; Ozgur Kasapcopur; Zeynep Coban Akdemir; Davut Pehlivan; Amber Begtrup; Claudia M.B. Carvalho; Ingrid Sophie Paine; Ali Mentes; Kivanc Bektas-Kayhan; Ender Karaca; Shalini N. Jhangiani; Donna M. Muzny; Richard A. Gibbs; James R. Lupski
      Pages: 149 - 156
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Yavuz Bayram, Janson J. White, Nursel Elcioglu, Megan T. Cho, Neda Zadeh, Asuman Gedikbasi, Sukru Palanduz, Sukru Ozturk, Kivanc Cefle, Ozgur Kasapcopur, Zeynep Coban Akdemir, Davut Pehlivan, Amber Begtrup, Claudia M.B. Carvalho, Ingrid Sophie Paine, Ali Mentes, Kivanc Bektas-Kayhan, Ender Karaca, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski
      Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3–p22.3, 5q13–q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.06.006
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 691 - 692
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.04.009
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 691 - 692
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.04.009
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 693 - 694
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Kathryn B. Garber

      PubDate: 2017-10-08T16:55:03Z
      DOI: 10.1016/j.ajhg.2017.04.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 693 - 694
      Abstract: Publication date: 7 September 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 3
      Author(s): Kathryn B. Garber

      PubDate: 2017-09-11T23:58:02Z
      DOI: 10.1016/j.ajhg.2017.04.006
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 567 - 568
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.03.007
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 569 - 570
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Kathryn B. Garber

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.03.006
  • Large-Scale Identification of Common Trait and Disease Variants Affecting
           Gene Expression
    • Authors: Mads Engel; Hauberg Wen Zhang Claudia Giambartolomei Oscar David Morris
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Mads Engel Hauberg, Wen Zhang, Claudia Giambartolomei, Oscar Franzén, David L. Morris, Timothy J. Vyse, Arno Ruusalepp, Pamela Sklar, Eric E. Schadt, Johan L.M. Björkegren, Panos Roussos

      PubDate: 2017-10-08T16:55:03Z
  • Spatial Clustering of de Novo Missense Mutations Identifies Candidate
           Neurodevelopmental Disorder-Associated Genes
    • Authors: Stefan H. Lelieveld; Laurens Wiel; Hanka Venselaar; Rolph Pfundt; Gerrit Vriend; Joris A. Veltman; Han G. Brunner; Lisenka E.L.M. Vissers; Christian Gilissen
      Abstract: Publication date: Available online 31 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Stefan H. Lelieveld, Laurens Wiel, Hanka Venselaar, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Han G. Brunner, Lisenka E.L.M. Vissers, Christian Gilissen
      Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.

      PubDate: 2017-09-05T23:53:22Z
      DOI: 10.1016/j.ajhg.2017.08.004
  • Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder
    • Authors: Deidre R. Krupp; Rebecca A. Barnard; Yannis Duffourd; Sara A. Evans; Ryan M. Mulqueen; Raphael Bernier; Jean-Baptiste Rivière; Eric Fombonne; Brian J. O’Roak
      Abstract: Publication date: Available online 31 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Deidre R. Krupp, Rebecca A. Barnard, Yannis Duffourd, Sara A. Evans, Ryan M. Mulqueen, Raphael Bernier, Jean-Baptiste Rivière, Eric Fombonne, Brian J. O’Roak
      Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted.

      PubDate: 2017-09-05T23:53:22Z
      DOI: 10.1016/j.ajhg.2017.07.016
  • Unified Sequence-Based Association Tests Allowing for Multiple Functional
           Annotations and Meta-Analysis of Noncoding Variation in Metabochip Data
    • Authors: Zihuai He; Bin Xu; Seunggeun Lee; Iuliana Ionita-Laza
      Abstract: Publication date: Available online 24 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Zihuai He, Bin Xu, Seunggeun Lee, Iuliana Ionita-Laza
      Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Here, we have developed unified tests that can utilize multiple functional annotations simultaneously for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power in relation to existing dispersion and burden tests, and under certain circumstances they can even have improved power by learning a weight that better approximates the underlying disease model in a data-adaptive manner. The tests can be constructed with summary statistics of existing dispersion and burden tests for sequencing data, therefore allowing meta-analysis of multiple studies without sharing individual-level data. We applied the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals from eight studies for lipid traits. By incorporating the Eigen functional score, we detected significant associations between noncoding rare variants in SLC22A3 and low-density lipoprotein and total cholesterol, associations that are missed by standard dispersion and burden tests.

      PubDate: 2017-08-25T23:44:44Z
      DOI: 10.1016/j.ajhg.2017.07.011
  • The Genetic Legacy of Zoroastrianism in Iran and India: Insights into
           Population Structure, Gene Flow, and Selection
    • Authors: Saioa Mark; Thomas Lucy van Dorp Naser Ansari-Pour Sarah Stewart
      Abstract: Publication date: Available online 24 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Saioa López, Mark G. Thomas, Lucy van Dorp, Naser Ansari-Pour, Sarah Stewart, Abigail L. Jones, Erik Jelinek, Lounès Chikhi, Tudor Parfitt, Neil Bradman, Michael E. Weale, Garrett Hellenthal
      Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we find that Zoroastrians in Iran and India have increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we infer that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690–1390 CE and providing strong evidence that Iranian Zoroastrian ancestry was maintained primarily through the male line. By making use of the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE–746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report results, and challenges, from a genome-wide scan to identify genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases among these communities.

      PubDate: 2017-08-25T23:44:44Z
  • Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping
    • Authors: Carlo Vermeulen; Geert Geeven; Elzo de Wit; Marjon J.A.M. Verstegen; Rumo P.M. Jansen; Melissa van Kranenburg; Ewart de Bruijn; Sara L. Pulit; Evelien Kruisselbrink; Zahra Shahsavari; Davood Omrani; Fatemeh Zeinali; Hossein Najmabadi; Theodora Katsila; Christina Vrettou; George P. Patrinos; Joanne Traeger-Synodinos; Erik Splinter; Jeffrey M. Beekman; Sima Kheradmand Kia; Gerard J. te Meerman; Hans Kristian Ploos van Amstel; Wouter de Laat
      Abstract: Publication date: Available online 24 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Carlo Vermeulen, Geert Geeven, Elzo de Wit, Marjon J.A.M. Verstegen, Rumo P.M. Jansen, Melissa van Kranenburg, Ewart de Bruijn, Sara L. Pulit, Evelien Kruisselbrink, Zahra Shahsavari, Davood Omrani, Fatemeh Zeinali, Hossein Najmabadi, Theodora Katsila, Christina Vrettou, George P. Patrinos, Joanne Traeger-Synodinos, Erik Splinter, Jeffrey M. Beekman, Sima Kheradmand Kia, Gerard J. te Meerman, Hans Kristian Ploos van Amstel, Wouter de Laat
      During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a blood sample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest. Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetal gene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict the inherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy of parental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robust method that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenic disease with a prenatal diagnostic test based on a simple blood draw.

      PubDate: 2017-08-25T23:44:44Z
      DOI: 10.1016/j.ajhg.2017.07.012
  • A Scalable Bayesian Method for Integrating Functional Information in
           Genome-wide Association Studies
    • Authors: Jingjing Yang; Lars Fritsche Xiang Zhou Abecasis
      Abstract: Publication date: Available online 24 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Jingjing Yang, Lars G. Fritsche, Xiang Zhou, Gonçalo Abecasis
      Genome-wide association studies (GWASs) have identified many complex loci. However, most loci reside in noncoding regions and have unknown biological functions. Integrative analysis that incorporates known functional information into GWASs can help elucidate the underlying biological mechanisms and prioritize important functional variants. Hence, we develop a flexible Bayesian variable selection model with efficient computational techniques for such integrative analysis. Different from previous approaches, our method models the effect-size distribution and probability of causality for variants with different annotations and jointly models genome-wide variants to account for linkage disequilibrium (LD), thus prioritizing associations based on the quantification of the annotations and allowing for multiple associated variants per locus. Our method dramatically improves both computational speed and posterior sampling convergence by taking advantage of the block-wise LD structures in human genomes. In simulations, our method accurately quantifies the functional enrichment and performs more powerfully for prioritizing the true associations than alternative methods, where the power gain is especially apparent when multiple associated variants in LD reside in the same locus. We applied our method to an in-depth GWAS of age-related macular degeneration with 33,976 individuals and 9,857,286 variants. We find the strongest enrichment for causality among non-synonymous variants (54× more likely to be causal, 1.4× larger effect sizes) and variants in transcription, repressed Polycomb, and enhancer regions, as well as identify five additional candidate loci beyond the 32 known AMD risk loci. In conclusion, our method is shown to efficiently integrate functional information in GWASs, helping identify functional associated-variants and underlying biology.

      PubDate: 2017-08-25T23:44:44Z
  • Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of
           Pontocerebellar Hypoplasia
    • Authors: Isaac Marin-Valencia; Andreas Gerondopoulos; Maha S. Zaki; Tawfeg Ben-Omran; Mariam Almureikhi; Ercan Demir; Alicia Guemez-Gamboa; Anne Gregor; Mahmoud Y. Issa; Bart Appelhof; Susanne Roosing; Damir Musaev; Basak Rosti; Sara Wirth; Valentina Stanley; Frank Baas; Francis A. Barr; Joseph G. Gleeson
      Abstract: Publication date: Available online 17 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Isaac Marin-Valencia, Andreas Gerondopoulos, Maha S. Zaki, Tawfeg Ben-Omran, Mariam Almureikhi, Ercan Demir, Alicia Guemez-Gamboa, Anne Gregor, Mahmoud Y. Issa, Bart Appelhof, Susanne Roosing, Damir Musaev, Basak Rosti, Sara Wirth, Valentina Stanley, Frank Baas, Francis A. Barr, Joseph G. Gleeson
      Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

      PubDate: 2017-08-25T23:44:44Z
      DOI: 10.1016/j.ajhg.2017.07.015
  • Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia
           and Alter Cortical Development
    • Authors: Ekaterina L. Ivanova; Frédéric Tran Mau-Them; Saima Riazuddin; Kimia Kahrizi; Vincent Laugel; Elise Schaefer; Anne de Saint Martin; Karen Runge; Zafar Iqbal; Marie-Aude Spitz; Mary Laura; Nathalie Drouot; Bénédicte Gérard; Jean-François Deleuze; Arjan P.M. de Brouwer; Attia Razzaq; Hélène Dollfus; Muhammad Zaman Assir; Patrick Nitchké; Maria-Victoria Hinckelmann; Hilger Ropers; Sheikh Riazuddin; Hossein Najmabadi; Hans van Bokhoven; Jamel Chelly
      Abstract: Publication date: Available online 17 August 2017
      Source:The American Journal of Human Genetics
      Author(s): Ekaterina L. Ivanova, Frédéric Tran Mau-Them, Saima Riazuddin, Kimia Kahrizi, Vincent Laugel, Elise Schaefer, Anne de Saint Martin, Karen Runge, Zafar Iqbal, Marie-Aude Spitz, Mary Laura, Nathalie Drouot, Bénédicte Gérard, Jean-François Deleuze, Arjan P.M. de Brouwer, Attia Razzaq, Hélène Dollfus, Muhammad Zaman Assir, Patrick Nitchké, Maria-Victoria Hinckelmann, Hilger Ropers, Sheikh Riazuddin, Hossein Najmabadi, Hans van Bokhoven, Jamel Chelly
      Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

      PubDate: 2017-08-25T23:44:44Z
      DOI: 10.1016/j.ajhg.2017.07.010
  • Continuity and Admixture in the Last Five Millennia of Levantine History
           from Ancient Canaanite and Present-Day Lebanese Genome Sequences
    • Authors: Marc Haber; Claude Doumet-Serhal Christiana Scheib Yali Xue Petr Danecek
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, 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
      The Canaanites inhabited the Levant region during the Bronze Age and established a culture that became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole genomes from ∼3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalog modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600–3,550 years ago, coinciding with recorded massive population movements in Mesopotamia during the mid-Holocene. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate that this Eurasian ancestry arrived in the Levant around 3,750–2,170 years ago during a period of successive conquests by distant populations.

      PubDate: 2017-08-05T22:39:11Z
  • Computational Prediction of Position Effects of Apparently Balanced Human
           Chromosomal Rearrangements
    • Authors: Cinthya J. Zepeda-Mendoza; Jonas Ibn-Salem; Tammy Kammin; David J. Harris; Debra Rita; Karen W. Gripp; Jennifer J. MacKenzie; Andrea Gropman; Brett Graham; Ranad Shaheen; Fowzan S. Alkuraya; Campbell K. Brasington; Edward J. Spence; Diane Masser-Frye; Lynne M. Bird; Erica Spiegel; Rebecca L. Sparkes; Zehra Ordulu; Michael E. Talkowski; Miguel A. Andrade-Navarro; Peter N. Robinson; Cynthia C. Morton
      Abstract: Publication date: Available online 20 July 2017
      Source:The American Journal of Human Genetics
      Author(s): Cinthya J. Zepeda-Mendoza, Jonas Ibn-Salem, Tammy Kammin, David J. Harris, Debra Rita, Karen W. Gripp, Jennifer J. MacKenzie, Andrea Gropman, Brett Graham, Ranad Shaheen, Fowzan S. Alkuraya, Campbell K. Brasington, Edward J. Spence, Diane Masser-Frye, Lynne M. Bird, Erica Spiegel, Rebecca L. Sparkes, Zehra Ordulu, Michael E. Talkowski, Miguel A. Andrade-Navarro, Peter N. Robinson, Cynthia C. Morton
      Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects’ phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.

      PubDate: 2017-07-21T07:18:05Z
      DOI: 10.1016/j.ajhg.2017.06.011
  • CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1
           Expression via Thousands of Large, Programmed Genomic Deletions
    • Authors: Molly Gasperini; Gregory M. Findlay; Aaron McKenna; Jennifer H. Milbank; Choli Lee; Melissa D. Zhang; Darren A. Cusanovich; Jay Shendure
      Abstract: Publication date: Available online 14 July 2017
      Source:The American Journal of Human Genetics
      Author(s): Molly Gasperini, Gregory M. Findlay, Aaron McKenna, Jennifer H. Milbank, Choli Lee, Melissa D. Zhang, Darren A. Cusanovich, Jay Shendure
      The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion (“ScanDel”). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.

      PubDate: 2017-07-21T07:18:05Z
      DOI: 10.1016/j.ajhg.2017.06.010
  • Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause
           Intellectual Disability or Epileptic Encephalopathy
    • Authors: Anna Lehman; Samrat Thouta; Grazia M.S. Mancini; Sakkubai Naidu; Marjon van Slegtenhorst; Kirsty McWalter; Richard Person; Jill Mwenifumbo; Ramona Salvarinova; Ilaria Guella; Marna B. McKenzie; Anita Datta; Mary B. Connolly; Somayeh Mojard Kalkhoran; Damon Poburko; Jan M. Friedman; Matthew J. Farrer; Michelle Demos; Sonal Desai; Thomas Claydon; Shelin Adam; Christèle du Souich; Alison M. Elliott; Anna Lehman; Jill Mwenifumbo; Tanya N. Nelson; Clara van Karnebeek; Jan M. Friedman; Shelin Adam; Cyrus Boelman; Corneliu Bolbocean; Sarah E. Buerki; Tara Candido; Patrice Eydoux; Daniel M. Evans; William Gibson; Gabriella Horvath; Linda Huh; Tanya N. Nelson; Graham Sinclair; Tamsin Tarling; Eric B. Toyota; Katelin N. Townsend; Margot I. Van Allen; Clara van Karnebeek; Suzanne Vercauteren
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Anna Lehman, Samrat Thouta, Grazia M.S. Mancini, Sakkubai Naidu, Marjon van Slegtenhorst, Kirsty McWalter, Richard Person, Jill Mwenifumbo, Ramona Salvarinova, Ilaria Guella, Marna B. McKenzie, Anita Datta, Mary B. Connolly, Somayeh Mojard Kalkhoran, Damon Poburko, Jan M. Friedman, Matthew J. Farrer, Michelle Demos, Sonal Desai, Thomas Claydon
      KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.016
  • Ultra-sensitive Sequencing Identifies High Prevalence of Clonal
           Hematopoiesis-Associated Mutations throughout Adult Life
    • Authors: Rocio Acuna-Hidalgo; Hilal Sengul; Marloes Steehouwer; Maartje van de Vorst; Sita H. Vermeulen; Lambertus A.L.M. Kiemeney; Joris A. Veltman; Christian Gilissen; Alexander Hoischen
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Rocio Acuna-Hidalgo, Hilal Sengul, Marloes Steehouwer, Maartje van de Vorst, Sita H. Vermeulen, Lambertus A.L.M. Kiemeney, Joris A. Veltman, Christian Gilissen, Alexander Hoischen
      Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay’s improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.013
  • Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert
           Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish
    • Authors: Julie C. Van De Weghe; Tamara D.S. Rusterholz; Brooke Latour; Megan E. Grout; Kimberly A. Aldinger; Ranad Shaheen; Jennifer C. Dempsey; Sateesh Maddirevula; Yong-Han H. Cheng; Ian G. Phelps; Matthias Gesemann; Himanshu Goel; Ohad S. Birk; Talal Alanzi; Rifaat Rawashdeh; Arif O. Khan; Michael J. Bamshad; Deborah A. Nickerson; Stephan C.F. Neuhauss; William B. Dobyns; Fowzan S. Alkuraya; Ronald Roepman; Ruxandra Bachmann-Gagescu; Dan Doherty
      Abstract: Publication date: Available online 15 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Julie C. Van De Weghe, Tamara D.S. Rusterholz, Brooke Latour, Megan E. Grout, Kimberly A. Aldinger, Ranad Shaheen, Jennifer C. Dempsey, Sateesh Maddirevula, Yong-Han H. Cheng, Ian G. Phelps, Matthias Gesemann, Himanshu Goel, Ohad S. Birk, Talal Alanzi, Rifaat Rawashdeh, Arif O. Khan, Michael J. Bamshad, Deborah A. Nickerson, Stephan C.F. Neuhauss, William B. Dobyns, Fowzan S. Alkuraya, Ronald Roepman, Ruxandra Bachmann-Gagescu, Dan Doherty
      Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the “molar tooth sign” on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

      PubDate: 2017-06-17T06:37:25Z
      DOI: 10.1016/j.ajhg.2017.05.010
  • A Fast and Accurate Algorithm to Test for Binary Phenotypes and Its
           Application to PheWAS
    • Authors: Rounak Dey; Ellen Schmidt Goncalo Abecasis Seunggeun Lee
      Abstract: Publication date: Available online 8 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Rounak Dey, Ellen M. Schmidt, Goncalo R. Abecasis, Seunggeun Lee
      The availability of electronic health record (EHR)-based phenotypes allows for genome-wide association analyses in thousands of traits and has great potential to enable identification of genetic variants associated with clinical phenotypes. We can interpret the phenome-wide association study (PheWAS) result for a single genetic variant by observing its association across a landscape of phenotypes. Because a PheWAS can test thousands of binary phenotypes, and most of them have unbalanced or often extremely unbalanced case-control ratios (1:10 or 1:600, respectively), existing methods cannot provide an accurate and scalable way to test for associations. Here, we propose a computationally fast score-test-based method that estimates the distribution of the test statistic by using the saddlepoint approximation. Our method is much (∼100 times) faster than the state-of-the-art Firth’s test. It can also adjust for covariates and control type I error rates even when the case-control ratio is extremely unbalanced. Through application to PheWAS data from the Michigan Genomics Initiative, we show that the proposed method can control type I error rates while replicating previously known association signals even for traits with a very small number of cases and a large number of controls.

      PubDate: 2017-06-17T06:37:25Z
School of Mathematical and Computer Sciences
Heriot-Watt University
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