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Showing 1 - 200 of 3175 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 8)
AASRI Procedia     Open Access   (Followers: 14)
Academic Pediatrics     Hybrid Journal   (Followers: 28, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 90, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 33, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 376, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 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  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 25, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 6)
Acute Pain     Full-text available via subscription   (Followers: 14)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 7)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 129, 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: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 12, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 27, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, 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: 14, 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: 2, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 28, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 7, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 3)
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: 27, 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: 10, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 14)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 10)
Advances in Digestive Medicine     Open Access   (Followers: 8)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Ecological Research     Full-text available via subscription   (Followers: 42, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 27, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 6)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 42, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 54, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Genetics     Full-text available via subscription   (Followers: 14, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 7)
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: 21, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 1, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 14, 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: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
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: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
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: 6, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, 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: 10)
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: 7)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 59)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 374, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 9, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 29, 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: 46, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 333, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 9, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 429, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 43, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 1)
Agriculture and Natural Resources     Open Access   (Followers: 2)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 56, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 9, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 5, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 50, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 50, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 42, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 42, 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: 190, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 62, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 27, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 37, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 61, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 14)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 39, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 166, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 10, 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   (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  [3175 journals]
  • Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial
           Presequence Protease Cause Neurodegeneration in Early Childhood
    • Authors: F.-Nora Vögtle; Björn Brändl; Austin Larson; Manuela Pendziwiat; Marisa W. Friederich; Susan M. White; Alice Basinger; Cansu Kücükköse; Hiltrud Muhle; Johanna A. Jähn; Oliver Keminer; Katherine L. Helbig; Carolyn F. Delto; Lisa Myketin; Dirk Mossmann; Nils Burger; Noriko Miyake; Audrey Burnett; Andreas van Baalen; Mark A. Lovell; Naomichi Matsumoto; Maie Walsh; Hung-Chun Yu; Deepali N. Shinde; Ulrich Stephani; Johan L.K. Van Hove; Franz-Josef Müller; Ingo Helbig
      Pages: 557 - 573
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): F.-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A. Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N. Shinde, Ulrich Stephani, Johan L.K. Van Hove, Franz-Josef Müller, Ingo Helbig
      Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.014
  • L-GATOR: Genetic Association Testing for a Longitudinally Measured
           Quantitative Trait in Samples with Related Individuals
    • Authors: Xiaowei Wu; Mary Sara McPeek
      Pages: 574 - 591
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Xiaowei Wu, Mary Sara McPeek
      In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals. L-GATOR allows arbitrary time points for different individuals, incorporates both time-varying and static covariates, and properly addresses various types of dependence. In simulations, we show that L-GATOR outperforms existing prospective methods in terms of both type 1 error and power when there is phenotype model misspecification or missing data. Compared with the previously proposed longGWAS method, L-GATOR was more than ten times faster for association testing in our simulations and almost 100 times faster for parameter estimation. L-GATOR is applicable to essentially arbitrary combinations of related and unrelated individuals, including small families as well as large, complex pedigrees. We apply the method to data from the Framingham Heart Study to identify association between longitudinal systolic blood pressure measurements and genome-wide SNPs. Of the smallest p values, one-third occur in or near genes that have been previously identified as associated with pulse pressure (such as PIK3CG) and systolic and diastolic blood pressure (such as C10orf107), showing that L-GATOR is able to prioritize relevant loci in a genome screen.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.016
  • PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses
           and Clinical Measures across 38,662 Individuals from Geisinger
    • Authors: Anurag Verma; Anastasia Lucas; Shefali S. Verma; Yu Zhang; Navya Josyula; Anqa Khan; Dustin N. Hartzel; Daniel R. Lavage; Joseph Leader; Marylyn D. Ritchie; Sarah A. Pendergrass
      Pages: 592 - 608
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Anurag Verma, Anastasia Lucas, Shefali S. Verma, Yu Zhang, Navya Josyula, Anqa Khan, Dustin N. Hartzel, Daniel R. Lavage, Joseph Leader, Marylyn D. Ritchie, Sarah A. Pendergrass
      Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency > 0.01 for 38,662 individuals. In this landscape PheWAS, we explored results within diseases and traits, comparing results to those previously reported in genome-wide association studies (GWASs), as well as previously published PheWASs. We further leveraged the context of functional impact from protein-coding to regulatory regions, providing a deeper interpretation of these associations. The comprehensive nature of this PheWAS allows for novel hypothesis generation, the identification of phenotypes for further study for future phenotypic algorithm development, and identification of cross-phenotype associations.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.017
  • Identification of Misclassified ClinVar Variants via Disease Population
    • Authors: Naisha Shah; Ying-Chen Claire Hou; Hung-Chun Yu; Rachana Sainger; C. Thomas Caskey; J. Craig Venter; Amalio Telenti
      Pages: 609 - 619
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Naisha Shah, Ying-Chen Claire Hou, Hung-Chun Yu, Rachana Sainger, C. Thomas Caskey, J. Craig Venter, Amalio Telenti
      There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). Inflation increases as the level of evidence supporting the pathogenic nature of the variant decreases. We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.019
  • A Common Type 2 Diabetes Risk Variant Potentiates Activity of an
           Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and
           C2CD4B Expression
    • Authors: Ina Kycia; Brooke N. Wolford; Jeroen R. Huyghe; Christian Fuchsberger; Swarooparani Vadlamudi; Romy Kursawe; Ryan P. Welch; Ricardo d’Oliveira Albanus; Asli Uyar; Shubham Khetan; Nathan Lawlor; Mohan Bolisetty; Anubhuti Mathur; Johanna Kuusisto; Markku Laakso; Duygu Ucar; Karen L. Mohlke; Michael Boehnke; Francis S. Collins; Stephen C.J. Parker; Michael L. Stitzel
      Pages: 620 - 635
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Ina Kycia, Brooke N. Wolford, Jeroen R. Huyghe, Christian Fuchsberger, Swarooparani Vadlamudi, Romy Kursawe, Ryan P. Welch, Ricardo d’Oliveira Albanus, Asli Uyar, Shubham Khetan, Nathan Lawlor, Mohan Bolisetty, Anubhuti Mathur, Johanna Kuusisto, Markku Laakso, Duygu Ucar, Karen L. Mohlke, Michael Boehnke, Francis S. Collins, Stephen C.J. Parker, Michael L. Stitzel
      Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10−17) variants in high linkage disequilibrium (r2 > 0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet and β cell stretch or super enhancer; the most strongly associated variant (rs7163757, p = 3 × 10−19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed 2-fold higher enhancer activity than the non-risk allele in reporter assays (p < 0.01) and was differentially bound by β cell nuclear extract proteins. Transcription factor NFAT specifically potentiated risk-allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting that it could be a factor mediating risk-allele effects. Finally, the rs7163757 proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets. Together, these data suggest that rs7163757 contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.020
  • Absence of CFAP69 Causes Male Infertility due to Multiple Morphological
           Abnormalities of the Flagella in Human and Mouse
    • Authors: Frederick N. Dong; Amir Amiri-Yekta; Guillaume Martinez; Antoine Saut; Julie Tek; Laurence Stouvenel; Patrick Lorès; Thomas Karaouzène; Nicolas Thierry-Mieg; Véronique Satre; Sophie Brouillet; Abbas Daneshipour; Seyedeh Hanieh Hosseini; Mélanie Bonhivers; Hamid Gourabi; Emmanuel Dulioust; Christophe Arnoult; Aminata Touré; Pierre F. Ray; Haiqing Zhao; Charles Coutton
      Pages: 636 - 648
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Frederick N. Dong, Amir Amiri-Yekta, Guillaume Martinez, Antoine Saut, Julie Tek, Laurence Stouvenel, Patrick Lorès, Thomas Karaouzène, Nicolas Thierry-Mieg, Véronique Satre, Sophie Brouillet, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Mélanie Bonhivers, Hamid Gourabi, Emmanuel Dulioust, Christophe Arnoult, Aminata Touré, Pierre F. Ray, Haiqing Zhao, Charles Coutton
      The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF. CFAP69 encodes an evolutionarily conserved protein found at high levels in the testis. Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations. Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype. Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis. Together, our data indicate that CFAP69 is necessary for flagellum assembly/stability and that in both humans and mice, biallelic truncating mutations in CFAP69 cause autosomal-recessive MMAF and primary male infertility.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.03.007
  • Homozygous Mutations in WEE2 Cause Fertilization Failure and Female
    • Authors: Qing Sang; Bin Li; Yanping Kuang; Xueqian Wang; Zhihua Zhang; Biaobang Chen; Ling Wu; Qifeng Lyu; Yonglun Fu; Zheng Yan; Xiaoyan Mao; Yao Xu; Jian Mu; Qiaoli Li; Li Jin; Lin He; Lei Wang
      Pages: 649 - 657
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang Chen, Ling Wu, Qifeng Lyu, Yonglun Fu, Zheng Yan, Xiaoyan Mao, Yao Xu, Jian Mu, Qiaoli Li, Li Jin, Lin He, Lei Wang
      Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. Wee2 is a key oocyte-specific kinase involved in the control of meiotic arrest in mice, but WEE2 has not been associated with any diseases in humans. In this study, we identified homozygous mutations in WEE2 that are responsible for fertilization failure in humans. All four independent affected individuals had homozygous loss-of-function missense mutations or homozygous frameshift protein-truncating mutations, and the phenotype of fertilization failure was shown to follow a Mendelian recessive inheritance pattern. All four mutations significantly decreased the amount of WEE2 protein in vitro and in affected individuals’ oocytes in vivo, and they all led to abnormal serine phosphorylation of WEE2 and reduced tyrosine 15 phosphorylation of Cdc2 in vitro. In addition, injection of WEE2 cRNA into affected individuals’ oocytes rescued the fertilization failure phenotype and led to the formation of blastocysts in vitro. This work presents a novel gene responsible for human fertilization failure and has implications for future therapeutic treatments for infertility cases.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.015
  • Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA
           Synthetase, Cause a Hypomyelinating Leukodystrophy
    • Authors: Marisa I. Mendes; Mariana Gutierrez Salazar; Kether Guerrero; Isabelle Thiffault; Gajja S. Salomons; Laurence Gauquelin; Luan T. Tran; Diane Forget; Marie-Soleil Gauthier; Quinten Waisfisz; Desiree E.C. Smith; Cas Simons; Marjo S. van der Knaap; Iris Marquardt; Aida Lemes; Hanna Mierzewska; Bernhard Weschke; Wolfgang Koehler; Benoit Coulombe; Nicole I. Wolf; Geneviève Bernard
      Pages: 676 - 684
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Marisa I. Mendes, Mariana Gutierrez Salazar, Kether Guerrero, Isabelle Thiffault, Gajja S. Salomons, Laurence Gauquelin, Luan T. Tran, Diane Forget, Marie-Soleil Gauthier, Quinten Waisfisz, Desiree E.C. Smith, Cas Simons, Marjo S. van der Knaap, Iris Marquardt, Aida Lemes, Hanna Mierzewska, Bernhard Weschke, Wolfgang Koehler, Benoit Coulombe, Nicole I. Wolf, Geneviève Bernard
      Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual’s lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.011
  • Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause
           Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex
    • Authors: Thatjana Gardeitchik; Miski Mohamed; Benedetta Ruzzenente; Daniela Karall; Sergio Guerrero-Castillo; Daisy Dalloyaux; Mariël van den Brand; Sanne van Kraaij; Ellyze van Asbeck; Zahra Assouline; Marlene Rio; Pascale de Lonlay; Sabine Scholl-Buergi; David F.G.J. Wolthuis; Alexander Hoischen; Richard J. Rodenburg; Wolfgang Sperl; Zsolt Urban; Ulrich Brandt; Johannes A. Mayr; Sunnie Wong; Arjan P.M. de Brouwer; Leo Nijtmans; Arnold Munnich; Agnès Rötig; Ron A. Wevers; Metodi D. Metodiev; Eva Morava
      Pages: 685 - 695
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Thatjana Gardeitchik, Miski Mohamed, Benedetta Ruzzenente, Daniela Karall, Sergio Guerrero-Castillo, Daisy Dalloyaux, Mariël van den Brand, Sanne van Kraaij, Ellyze van Asbeck, Zahra Assouline, Marlene Rio, Pascale de Lonlay, Sabine Scholl-Buergi, David F.G.J. Wolthuis, Alexander Hoischen, Richard J. Rodenburg, Wolfgang Sperl, Zsolt Urban, Ulrich Brandt, Johannes A. Mayr, Sunnie Wong, Arjan P.M. de Brouwer, Leo Nijtmans, Arnold Munnich, Agnès Rötig, Ron A. Wevers, Metodi D. Metodiev, Eva Morava
      Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects’ fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects’ muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.012
  • Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and
           Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos
    • Authors: Patrick R. Blackburn; Zhi Xu; Kathleen E. Tumelty; Rose W. Zhao; William J. Monis; Kimberly G. Harris; Jennifer M. Gass; Margot A. Cousin; Nicole J. Boczek; Mario V. Mitkov; Mark A. Cappel; Clair A. Francomano; Joseph E. Parisi; Eric W. Klee; Eissa Faqeih; Fowzan S. Alkuraya; Matthew D. Layne; Nazli B. McDonnell; Paldeep S. Atwal
      Pages: 696 - 705
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Patrick R. Blackburn, Zhi Xu, Kathleen E. Tumelty, Rose W. Zhao, William J. Monis, Kimberly G. Harris, Jennifer M. Gass, Margot A. Cousin, Nicole J. Boczek, Mario V. Mitkov, Mark A. Cappel, Clair A. Francomano, Joseph E. Parisi, Eric W. Klee, Eissa Faqeih, Fowzan S. Alkuraya, Matthew D. Layne, Nazli B. McDonnell, Paldeep S. Atwal
      AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 −/− mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581∗]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs∗3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.02.018
  • LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic
           Aneurysms and Dissections
    • Authors: Dong-chuan Guo; Ellen S. Regalado; Amelie Pinard; Jiyuan Chen; Kwanghyuk Lee; Christina Rigelsky; Lior Zilberberg; Ellen M. Hostetler; Micheala Aldred; Stephanie E. Wallace; Siddharth K. Prakash; Suzanne M. Leal; Michael J. Bamshad; Deborah A. Nickerson; Marvin Natowicz; Daniel B. Rifkin; Dianna M. Milewicz
      Pages: 706 - 712
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan Chen, Kwanghyuk Lee, Christina Rigelsky, Lior Zilberberg, Ellen M. Hostetler, Micheala Aldred, Stephanie E. Wallace, Siddharth K. Prakash, Suzanne M. Leal, Michael J. Bamshad, Deborah A. Nickerson, Marvin Natowicz, Daniel B. Rifkin, Dianna M. Milewicz
      The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 −/− mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.03.002
  • Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype
           Associated with Early-Onset Retinitis Pigmentosa
    • Authors: Andrea Angius; Paolo Uva; Insa Buers; Manuela Oppo; Alessandro Puddu; Stefano Onano; Ivana Persico; Angela Loi; Loredana Marcia; Wolfgang Höhne; Gianmauro Cuccuru; Giorgio Fotia; Manila Deiana; Mara Marongiu; Hatice Tuba Atalay; Sibel Inan; Osama El Assy; Leo M.E. Smit; Ilyas Okur; Koray Boduroglu; Gülen Eda Utine; Esra Kılıç; Giuseppe Zampino; Giangiorgio Crisponi; Laura Crisponi; Frank Rutsch
      First page: 713
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Andrea Angius, Paolo Uva, Insa Buers, Manuela Oppo, Alessandro Puddu, Stefano Onano, Ivana Persico, Angela Loi, Loredana Marcia, Wolfgang Höhne, Gianmauro Cuccuru, Giorgio Fotia, Manila Deiana, Mara Marongiu, Hatice Tuba Atalay, Sibel Inan, Osama El Assy, Leo M.E. Smit, Ilyas Okur, Koray Boduroglu, Gülen Eda Utine, Esra Kılıç, Giuseppe Zampino, Giangiorgio Crisponi, Laura Crisponi, Frank Rutsch

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.03.020
  • 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 Boddaert; 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
      First page: 713
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      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 Boddaert, 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

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.03.015
  • Arno G. Motulsky (1923–2018): A Founder of Medical Genetics, Creator of
           Pharmacogenetics, and Former ASHG President
    • Authors: Gail P. Jarvik; Mary-Claire King
      Pages: 335 - 339
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Gail P. Jarvik, Mary-Claire King

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.02.005
  • 2017 Presidential Address: Checking, Balancing, and Celebrating Diversity:
           Celebrating Some of the Women Who Paved the Way1
    • Authors: Nancy J. Cox
      Pages: 342 - 349
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Nancy J. Cox

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.02.006
  • 2017 William Allan Award Introduction: Kári Stefansson1
    • Authors: Mark J. Daly
      First page: 350
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Mark J. Daly

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.010
  • 2017 William Allan Award1
    • Authors: Kári Stefansson
      Pages: 351 - 353
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Kári Stefansson

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.012
  • 2017 Curt Stern Award Introduction: Nico Katsanis1
    • Authors: Han G. Brunner
      First page: 354
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Han G. Brunner

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.013
  • 2017 Curt Stern Award: The Complexity of Simple Genetics1
    • Authors: Nicholas Katsanis
      Pages: 355 - 358
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Nicholas Katsanis

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.02.004
  • 2017 Victor A. McKusick Leadership Award Introduction: Arthur L. Beaudet1
    • Authors: Brendan Lee
      Pages: 359 - 360
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Brendan Lee

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.022
  • 2017 Victor A. McKusick Leadership Award1
    • Authors: Arthur L. Beaudet
      Pages: 361 - 363
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Arthur L. Beaudet

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.011
  • Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating
           Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
    • Authors: Clothilde Esteve; Ludmila Francescatto; Perciliz L. Tan; Aurélie Bourchany; Cécile De Leusse; Evelyne Marinier; Arnaud Blanchard; Patrice Bourgeois; Céline Brochier-Armanet; Ange-Line Bruel; Arnauld Delarue; Yannis Duffourd; Emmanuelle Ecochard-Dugelay; Géraldine Hery; Frédéric Huet; Philippe Gauchez; Emmanuel Gonzales; Catherine Guettier-Bouttier; Mina Komuta; Caroline Lacoste; Raphaelle Maudinas; Karin Mazodier; Yves Rimet; Jean-Baptiste Rivière; Bertrand Roquelaure; Sabine Sigaudy; Xavier Stephenne; Christel Thauvin-Robinet; Julien Thevenon; Jacques Sarles; Nicolas Levy; Catherine Badens; Olivier Goulet; Jean-Pierre Hugot; Nicholas Katsanis; Laurence Faivre; Alexandre Fabre
      Pages: 364 - 374
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aurélie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugelay, Géraldine Hery, Frédéric Huet, Philippe Gauchez, Emmanuel Gonzales, Catherine Guettier-Bouttier, Mina Komuta, Caroline Lacoste, Raphaelle Maudinas, Karin Mazodier, Yves Rimet, Jean-Baptiste Rivière, Bertrand Roquelaure, Sabine Sigaudy, Xavier Stephenne, Christel Thauvin-Robinet, Julien Thevenon, Jacques Sarles, Nicolas Levy, Catherine Badens, Olivier Goulet, Jean-Pierre Hugot, Nicholas Katsanis, Laurence Faivre, Alexandre Fabre
      Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.009
  • Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene
           Selection for Sporadic Parkinson Disease
    • Authors: Paul W. Hook; Sarah A. McClymont; Gabrielle H. Cannon; William D. Law; A. Jennifer Morton; Loyal A. Goff; Andrew S. McCallion
      Pages: 427 - 446
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Paul W. Hook, Sarah A. McClymont, Gabrielle H. Cannon, William D. Law, A. Jennifer Morton, Loyal A. Goff, Andrew S. McCallion
      Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.02.001
  • Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State
           Transition and Causes Posterior Polymorphous Corneal Dystrophy 4
    • Authors: Petra Liskova; Lubica Dudakova; Cerys J. Evans; Karla E. Rojas Lopez; Nikolas Pontikos; Dimitra Athanasiou; Hodan Jama; Josef Sach; Pavlina Skalicka; Viktor Stranecky; Stanislav Kmoch; Caroline Thaung; Martin Filipec; Michael E. Cheetham; Alice E. Davidson; Stephen J. Tuft; Alison J. Hardcastle
      Pages: 447 - 459
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Petra Liskova, Lubica Dudakova, Cerys J. Evans, Karla E. Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E. Cheetham, Alice E. Davidson, Stephen J. Tuft, Alison J. Hardcastle
      In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3–q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to-epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal “endothelium” in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.02.002
  • NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals
           with Leigh-like Encephalomyopathy
    • Authors: Dorota Piekutowska-Abramczuk; Zahra Assouline; Lavinija Mataković; René G. Feichtinger; Eliška Koňařiková; Elżbieta Jurkiewicz; Piotr Stawiński; Mirjana Gusic; Andreas Koller; Agnieszka Pollak; Piotr Gasperowicz; Joanna Trubicka; Elżbieta Ciara; Katarzyna Iwanicka-Pronicka; Dariusz Rokicki; Sylvain Hanein; Saskia B. Wortmann; Wolfgang Sperl; Agnès Rötig; Holger Prokisch; Ewa Pronicka; Rafał Płoski; Giulia Barcia; Johannes A. Mayr
      Pages: 460 - 467
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Dorota Piekutowska-Abramczuk, Zahra Assouline, Lavinija Mataković, René G. Feichtinger, Eliška Koňařiková, Elżbieta Jurkiewicz, Piotr Stawiński, Mirjana Gusic, Andreas Koller, Agnieszka Pollak, Piotr Gasperowicz, Joanna Trubicka, Elżbieta Ciara, Katarzyna Iwanicka-Pronicka, Dariusz Rokicki, Sylvain Hanein, Saskia B. Wortmann, Wolfgang Sperl, Agnès Rötig, Holger Prokisch, Ewa Pronicka, Rafał Płoski, Giulia Barcia, Johannes A. Mayr
      Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.008
  • Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris
    • Authors: Georgia Vasileiou; Silvia Vergarajauregui; Sabine Endele; Bernt Popp; Christian Büttner; Arif B. Ekici; Marion Gerard; Nuria C. Bramswig; Beate Albrecht; Jill Clayton-Smith; Jenny Morton; Susan Tomkins; Karen Low; Astrid Weber; Maren Wenzel; Janine Altmüller; Yun Li; Bernd Wollnik; George Hoganson; Maria-Renée Plona; Megan T. Cho; Christian T. Thiel; Hermann-Josef Lüdecke; Tim M. Strom; Eduardo Calpena; Andrew O.M. Wilkie; Dagmar Wieczorek; Felix B. Engel; André Reis
      Pages: 468 - 479
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Georgia Vasileiou, Silvia Vergarajauregui, Sabine Endele, Bernt Popp, Christian Büttner, Arif B. Ekici, Marion Gerard, Nuria C. Bramswig, Beate Albrecht, Jill Clayton-Smith, Jenny Morton, Susan Tomkins, Karen Low, Astrid Weber, Maren Wenzel, Janine Altmüller, Yun Li, Bernd Wollnik, George Hoganson, Maria-Renée Plona, Megan T. Cho, Christian T. Thiel, Hermann-Josef Lüdecke, Tim M. Strom, Eduardo Calpena, Andrew O.M. Wilkie, Dagmar Wieczorek, Felix B. Engel, André Reis
      Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.014
  • Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2
    • Authors: Petra Lassuthova; Adriana P. Rebelo; Gianina Ravenscroft; Phillipa J. Lamont; Mark R. Davis; Fiore Manganelli; Shawna M. Feely; Chelsea Bacon; Dana Šafka Brožková; Jana Haberlova; Radim Mazanec; Feifei Tao; Cima Saghira; Lisa Abreu; Steve Courel; Eric Powell; Elena Buglo; Dana M. Bis; Megan F. Baxter; Royston W. Ong; Lorna Marns; Yi-Chung Lee; Yunhong Bai; Daniel G. Isom; René Barro-Soria; Ki W. Chung; Steven S. Scherer; H. Peter Larsson; Nigel G. Laing; Byung-Ok Choi; Pavel Seeman; Michael E. Shy; Lucio Santoro; Stephan Zuchner
      Pages: 505 - 514
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Petra Lassuthova, Adriana P. Rebelo, Gianina Ravenscroft, Phillipa J. Lamont, Mark R. Davis, Fiore Manganelli, Shawna M. Feely, Chelsea Bacon, Dana Šafka Brožková, Jana Haberlova, Radim Mazanec, Feifei Tao, Cima Saghira, Lisa Abreu, Steve Courel, Eric Powell, Elena Buglo, Dana M. Bis, Megan F. Baxter, Royston W. Ong, Lorna Marns, Yi-Chung Lee, Yunhong Bai, Daniel G. Isom, René Barro-Soria, Ki W. Chung, Steven S. Scherer, H. Peter Larsson, Nigel G. Laing, Byung-Ok Choi, Pavel Seeman, Michael E. Shy, Lucio Santoro, Stephan Zuchner
      Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way—by combining data from seven countries on four continents—we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.023
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 197 - 198
      Abstract: Publication date: 5 April 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 4
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2018-04-06T17:27:35Z
      DOI: 10.1016/j.ajhg.2018.01.007
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 197 - 198
      Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2018-03-07T14:11:09Z
      DOI: 10.1016/j.ajhg.2018.01.007
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 197 - 198
      Abstract: Publication date: 1 February 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 2
      Author(s): Sarah Ratzel, Sara B. Cullinan

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

      PubDate: 2018-02-05T07:41:58Z
      DOI: 10.1016/j.ajhg.2017.12.017
  • Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of
    • Abstract: Publication date: Available online 12 April 2018
      Source:The American Journal of Human Genetics
      Author(s): Claire Guissart, Xenia Latypova, Paul Rollier, Tahir N. Khan, Hannah Stamberger, Kirsty McWalter, Megan T. Cho, Susanne Kjaergaard, Sarah Weckhuysen, Gaetan Lesca, Thomas Besnard, Katrin Õunap, Lynn Schema, Andreas G. Chiocchetti, Marie McDonald, Julitta de Bellescize, Marie Vincent, Hilde Van Esch, Shannon Sattler, Irman Forghani, Isabelle Thiffault, Christine M. Freitag, Deborah Sara Barbouth, Maxime Cadieux-Dion, Rebecca Willaert, Maria J. Guillen Sacoto, Nicole P. Safina, Christèle Dubourg, Lauren Grote, Wilfrid Carré, Carol Saunders, Sander Pajusalu, Emily Farrow, Anne Boland, Danielle Hays Karlowicz, Jean-François Deleuze, Monica H. Wojcik, Rena Pressman, Bertrand Isidor, Annick Vogels, Wim Van Paesschen, Lihadh Al-Gazali, Aisha Mohamed Al Shamsi, Mireille Claustres, Aurora Pujol, Stephan J. Sanders, François Rivier, Nicolas Leboucq, Benjamin Cogné, Souphatta Sasorith, Damien Sanlaville, Kyle Retterer, Sylvie Odent, Nicholas Katsanis, Stéphane Bézieau, Michel Koenig, Erica E. Davis, Laurent Pasquier, Sébastien Küry
      RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

      PubDate: 2018-04-15T18:10:44Z
  • A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes
           Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism,
           and Cerebellar Dysgenesis
    • Abstract: Publication date: Available online 12 April 2018
      Source:The American Journal of Human Genetics
      Author(s): Heather E. Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Heron, Katrina Tatton-Brown, Paul A. van der Zwaag, Emilia K. Bijlsma, Bryan L. Krock, E. Backer, Erik-Jan Kamsteeg, Margje Sinnema, Margot R.F. Reijnders, David Bearden, Amber Begtrup, Aida Telegrafi, Roelineke J. Lunsing, Lydie Burglen, Gaetan Lesca, Megan T. Cho, Lacey A. Smith, Beth R. Sheidley, Christelle Moufawad El Achkar, Phillip L. Pearl, Annapurna Poduri, Cara M. Skraban, Jennifer Tarpinian, Addie I. Nesbitt, Dietje E. Fransen van de Putte, Claudia A.L. Ruivenkamp, Patrick Rump, Nicolas Chatron, Isabelle Sabatier, Julitta De Bellescize, Laurent Guibaud, David A. Sweetser, Jessica L. Waxler, Klaas J. Wierenga, Jean Donadieu, Vinodh Narayanan, Keri M. Ramsey, Caroline Nava, Jean-Baptiste Rivière, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Ange-Line Bruel, Yannis Duffourd, Laurel Thomas, Stefan H. Lelieveld, Janneke Schuurs-Hoeijmakers, Han G. Brunner, Boris Keren, Julien Thevenon, Laurence Faivre, Gary Thomas, Christel Thauvin-Robinet
      Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

      PubDate: 2018-04-15T18:10:44Z
  • Truncating Variants in NAA15 Are Associated with Variable Levels of
           Intellectual Disability, Autism Spectrum Disorder, and Congenital
    • Abstract: Publication date: Available online 12 April 2018
      Source:The American Journal of Human Genetics
      Author(s): Hanyin Cheng, Avinash V. Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F. Rope, Margaret Yoon, Asbjørg Stray-Pedersen, Jennifer E. Posey, Sarah R. Crews, Mohammad K. Eldomery, Zeynep Coban Akdemir, Andrea M. Lewis, Vernon R. Sutton, Jill A. Rosenfeld, Erin Conboy, Katherine Agre, Fan Xia, Magdalena Walkiewicz, Mauro Longoni, Frances A. High, Marjon A. van Slegtenhorst, Grazia M.S. Mancini, Candice R. Finnila, Arie van Haeringen, Nicolette den Hollander, Claudia Ruivenkamp, Sakkubai Naidu, Sonal Mahida, Elizabeth E. Palmer, Lucinda Murray, Derek Lim, Parul Jayakar, Michael J. Parker, Stefania Giusto, Emanuela Stracuzzi, Corrado Romano, Jennifer S. Beighley, Raphael A. Bernier, Sébastien Küry, Mathilde Nizon, Mark A. Corbett, Marie Shaw, Alison Gardner, Christopher Barnett, Ruth Armstrong, Karin S. Kassahn, Anke Van Dijck, Geert Vandeweyer, Tjitske Kleefstra, Jolanda Schieving, Marjolijn J. Jongmans, Bert B.A. de Vries, Rolph Pfundt, Bronwyn Kerr, Samantha K. Rojas, Kym M. Boycott, Richard Person, Rebecca Willaert, Evan E. Eichler, R. Frank Kooy, Yaping Yang, Joseph C. Wu, James R. Lupski, Thomas Arnesen, Gregory M. Cooper, Wendy K. Chung, Jozef Gecz, Holly A.F. Stessman, Linyan Meng, Gholson J. Lyon
      N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

      PubDate: 2018-04-15T18:10:44Z
  • Relationship between Deleterious Variation, Genomic Autozygosity, and
           Disease Risk: Insights from The 1000 Genomes Project
    • Authors: Trevor J. Pemberton; Zachary A. Szpiech
      Abstract: Publication date: Available online 15 March 2018
      Source:The American Journal of Human Genetics
      Author(s): Trevor J. Pemberton, Zachary A. Szpiech
      Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations—relatively untouched by purifying selection—being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome sequence data on 27 individuals. Here, we significantly bolster support for our hypothesis and expand upon our original analyses using ROA and whole-genome sequence data on 2,436 individuals from The 1000 Genomes Project. Considering CADD deleteriousness scores, we reaffirm our previous observation that long ROAs are enriched for damaging homozygotes worldwide. We show that strongly damaging homozygotes experience greater enrichment than weaker damaging homozygotes, while overall enrichment varies appreciably among populations. Mendelian disease genes and those encoding FDA-approved drug targets have significantly increased rates of gain in damaging homozygotes with increasing ROA coverage relative to all other genes. In genes implicated in eight complex phenotypes for which ROA levels have been identified as a risk factor, rates of gain in damaging homozygotes vary across phenotypes and populations but frequently differ significantly from non-disease genes. These findings highlight the potential confounding effects of population background in the assessment of associations between ROA levels and complex disease risk, which might underlie reported inconsistencies in ROA-phenotype associations.

      PubDate: 2018-03-19T15:20:42Z
      DOI: 10.1016/j.ajhg.2018.02.013
  • Outcomes of Counseling after Education about Carrier Results: A Randomized
           Controlled Trial
    • Authors: Katie L. Lewis; Kendall L. Umstead; Jennifer J. Johnston; Ilana M. Miller; Lydia J. Thompson; Kristen P. Fishler; Leslie G. Biesecker; Barbara B. Biesecker
      Abstract: Publication date: Available online 8 March 2018
      Source:The American Journal of Human Genetics
      Author(s): Katie L. Lewis, Kendall L. Umstead, Jennifer J. Johnston, Ilana M. Miller, Lydia J. Thompson, Kristen P. Fishler, Leslie G. Biesecker, Barbara B. Biesecker
      In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post-reproductive participants from the ClinSeq cohort within a randomized controlled trial. Participants received education and were randomized to receive counseling or not. Primary outcomes included risk worry, test-related positive experiences, attitudes, and decisional conflict. Secondary outcomes were satisfaction, preferences, and counseling value. There were no differences between participants who received counseling and those who did not in the primary outcomes. Participants who received counseling were more satisfied than those who did not ( x ¯ = 10.2 and 9.5, respectively, p < 0.002, range: 3–12), although overall satisfaction was high. Most participants (92%) randomized to counseling preferred it and valued it because it provided validation of their reactions and an opportunity for interpersonal interaction. Web-based tools address the challenge of returning low-impact results, and these data provide empiric evidence that counseling, although preferred and satisfying, is not critical to achieving desired outcomes.

      PubDate: 2018-03-19T15:20:42Z
      DOI: 10.1016/j.ajhg.2018.02.009
  • Identification and Rescue of Splice Defects Caused by Two Neighboring
           Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease
    • Authors: Silvia Albert; Alejandro Garanto; Riccardo Sangermano; Mubeen Khan; Nathalie M. Bax; Carel B. Hoyng; Jana Zernant; Winston Lee; Rando Allikmets; Rob W.J. Collin; Frans P.M. Cremers
      Abstract: Publication date: Available online 8 March 2018
      Source:The American Journal of Human Genetics
      Author(s): Silvia Albert, Alejandro Garanto, Riccardo Sangermano, Mubeen Khan, Nathalie M. Bax, Carel B. Hoyng, Jana Zernant, Winston Lee, Rando Allikmets, Rob W.J. Collin, Frans P.M. Cremers
      Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c.4539+2001G>A and c.4539+2028C>T) result in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs∗36), likely due to the creation of exonic enhancers. Administration of antisense oligonucleotides (AONs) targeting the 345-nt pseudoexon can significantly rescue the splicing defect observed in PPCs of two individuals with these mutations. Intriguingly, an AON that is complementary to c.4539+2001G>A rescued the splicing defect only in PPCs derived from an individual with STGD1 with this but not the other mutation, demonstrating the high specificity of AONs. In addition, a single AON molecule rescued splicing defects associated with different neighboring mutations, thereby providing new strategies for the treatment of persons with STGD1. As many genes associated with human genetic conditions are expressed in specific tissues and pre-mRNA splicing may also rely on organ-specific factors, our approach to investigate and treat splicing variants using differentiated cells derived from individuals with STGD1 can be applied to any tissue of interest.

      PubDate: 2018-03-19T15:20:42Z
      DOI: 10.1016/j.ajhg.2018.02.008
  • Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat
           Expansion-Mediated Toxicity
    • Authors: Christina Zarouchlioti; Beatriz Sanchez-Pintado; Nathaniel J. Hafford Tear; Pontus Klein; Petra Liskova; Kalyan Dulla; Ma’ayan Semo; Anthony A. Vugler; Kirithika Muthusamy; Lubica Dudakova; Hannah J. Levis; Pavlina Skalicka; Pirro Hysi; Michael E. Cheetham; Stephen J. Tuft; Peter Adamson; Alison J. Hardcastle; Alice E. Davidson
      Abstract: Publication date: Available online 8 March 2018
      Source:The American Journal of Human Genetics
      Author(s): Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J. Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma’ayan Semo, Anthony A. Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J. Levis, Pavlina Skalicka, Pirro Hysi, Michael E. Cheetham, Stephen J. Tuft, Peter Adamson, Alison J. Hardcastle, Alice E. Davidson
      Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.

      PubDate: 2018-03-19T15:20:42Z
      DOI: 10.1016/j.ajhg.2018.02.010
  • Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle
           Allele during the Holocene Wet Phase
    • Authors: Daniel Shriner; Charles Rotimi
      Abstract: Publication date: Available online 8 March 2018
      Source:The American Journal of Human Genetics
      Author(s): Daniel Shriner, Charles N. Rotimi
      Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB). We investigated the origins of the sickle mutation by using whole-genome-sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We classified haplotypes by using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic (CAR), Cameroon, and Arabian/Indian haplotypes. Other haplotypes were derived from this haplotype and fell into two clusters, one composed of Senegal haplotypes and the other composed of Benin and Senegal haplotypes. The near-exclusive presence of the original sickle haplotype in the CAR, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu expansions. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded a sickle mutation age of 259 generations, corresponding to 7,300 years ago during the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes.

      PubDate: 2018-03-19T15:20:42Z
  • 2017 ASHG Awards and Addresses
    • Abstract: Publication date: 1 March 2018
      Source:The American Journal of Human Genetics, Volume 102, Issue 3
      Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at

      PubDate: 2018-03-07T14:11:09Z
  • Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes
           Testis Development and Cardiac Defects in 46,XX Children
    • Authors: Anu Bashamboo; Caroline Eozenou; Anne Jorgensen; Joelle Bignon-Topalovic; Jean-Pierre Siffroi; Capucine Hyon; Attila Tar; Péter Nagy; Janos Sólyom; Zita Halász; Annnabel Paye-Jaouen; Sophie Lambert; David Rodriguez-Buritica; Rita Bertalan; Laetitia Martinerie; Ewa Rajpert-De Meyts; John C. Achermann; Ken McElreavey
      Abstract: Publication date: Available online 22 February 2018
      Source:The American Journal of Human Genetics
      Author(s): Anu Bashamboo, Caroline Eozenou, Anne Jorgensen, Joelle Bignon-Topalovic, Jean-Pierre Siffroi, Capucine Hyon, Attila Tar, Péter Nagy, Janos Sólyom, Zita Halász, Annnabel Paye-Jaouen, Sophie Lambert, David Rodriguez-Buritica, Rita Bertalan, Laetitia Martinerie, Ewa Rajpert-De Meyts, John C. Achermann, Ken McElreavey
      Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10−8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human “pro-ovary” and “anti-testis” sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

      PubDate: 2018-02-26T09:16:27Z
      DOI: 10.1016/j.ajhg.2018.01.021
  • Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase,
           Cause a Metabolic Disorder
    • Authors: Monika Wan; Hee Yoon Kyle Thompson Sharayu Jangam Liliana Fernandez
      Abstract: Publication date: Available online 22 February 2018
      Source:The American Journal of Human Genetics
      Author(s): Monika Oláhová, Wan Hee Yoon, Kyle Thompson, Sharayu Jangam, Liliana Fernandez, Jean M. Davidson, Jennifer E. Kyle, Megan E. Grove, Dianna G. Fisk, Jennefer N. Kohler, Matthew Holmes, Annika M. Dries, Yong Huang, Chunli Zhao, Kévin Contrepois, Zachary Zappala, Laure Frésard, Daryl Waggott, Erika M. Zink, Young-Mo Kim, Heino M. Heyman, Kelly G. Stratton, Bobbie-Jo M. Webb-Robertson, Michael Snyder, Jason D. Merker, Stephen B. Montgomery, Paul G. Fisher, René G. Feichtinger, Johannes A. Mayr, Julie Hall, Ines A. Barbosa, Michael A. Simpson, Charu Deshpande, Katrina M. Waters, David M. Koeller, Thomas O. Metz, Andrew A. Morris, Susan Schelley, Tina Cowan, Marisa W. Friederich, Robert McFarland, Johan L.K. Van Hove, Gregory M. Enns, Shinya Yamamoto, Euan A. Ashley, Michael F. Wangler, Robert W. Taylor, Hugo J. Bellen, Jonathan A. Bernstein, Matthew T. Wheeler
      ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

      PubDate: 2018-02-26T09:16:27Z
  • Inherited DNA-Repair Defects in Colorectal Cancer
    • Authors: Saud AlDubayan; Marios Giannakis Nathanael Moore Celine Han Brendan Reardon
      Abstract: Publication date: Available online 22 February 2018
      Source:The American Journal of Human Genetics
      Author(s): Saud H. AlDubayan, Marios Giannakis, Nathanael D. Moore, G. Celine Han, Brendan Reardon, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Reiko Nishihara, Zhirong Qian, Li Liu, Matthew B. Yurgelun, Sapna Syngal, Levi A. Garraway, Shuji Ogino, Charles S. Fuchs, Eliezer M. Van Allen
      Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi).

      PubDate: 2018-02-26T09:16:27Z
  • Comprehensive Analysis of Constraint on the Spatial Distribution of
           Missense Variants in Human Protein Structures
    • Authors: R. Michael Sivley; Xiaoyi Dou; Jens Meiler; William S. Bush; John A. Capra
      Abstract: Publication date: Available online 15 February 2018
      Source:The American Journal of Human Genetics
      Author(s): R. Michael Sivley, Xiaoyi Dou, Jens Meiler, William S. Bush, John A. Capra
      The spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and provides insight into the functional importance of protein regions and the potential pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of human germline and somatic variation in 6,604 experimentally derived protein structures and 33,144 computationally derived homology models covering 77% of all human proteins. Using a systematic approach, we quantify differences in the spatial distributions of neutral germline variants, disease-causing germline variants, and recurrent somatic variants. Neutral missense variants exhibit a general trend toward spatial dispersion, which is driven by constraint on core residues. In contrast, germline disease-causing variants are generally clustered in protein structures and form clusters more frequently than recurrent somatic variants identified from tumor sequencing. In total, we identify 215 proteins with significant spatial constraints on the distribution of disease-causing missense variants in experimentally derived protein structures, only 65 (30%) of which have been previously reported. This analysis identifies many clusters not detectable from sequence information alone; only 12% of proteins with significant clustering in 3D were identified from similar analyses of linear protein sequence. Furthermore, spatial analyses of mutations in homology-based structural models are highly correlated with those from experimentally derived structures, supporting the use of computationally derived models. Our approach highlights significant differences in the spatial constraints on different classes of mutations in protein structure and identifies regions of potential function within individual proteins.

      PubDate: 2018-02-26T09:16:27Z
      DOI: 10.1016/j.ajhg.2018.01.017
  • A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking
           Behavior Identifies Multiple Significant Loci for Blood Pressure
    • Authors: Yun Sung; Thomas Winkler Lisa las Fuentes Amy Bentley Michael
      Abstract: Publication date: Available online 15 February 2018
      Source:The American Journal of Human Genetics
      Author(s): Yun J. Sung, Thomas W. Winkler, Lisa de las Fuentes, Amy R. Bentley, Michael R. Brown, Aldi T. Kraja, Karen Schwander, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K. Musani, Changwei Li, Mary F. Feitosa, Tuomas O. Kilpeläinen, Melissa A. Richard, Raymond Noordam, Stella Aslibekyan, Hugues Aschard, Traci M. Bartz, Rajkumar Dorajoo, Yongmei Liu, Alisa K. Manning, Tuomo Rankinen, Albert Vernon Smith, Salman M. Tajuddin, Bamidele O. Tayo, Helen R. Warren, Wei Zhao, Yanhua Zhou, Nana Matoba, Tamar Sofer, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Ilaria Gandin, Chuan Gao, Franco Giulianini, Anuj Goel, Sarah E. Harris, Fernando Pires Hartwig, Andrea R.V.R. Horimoto, Fang-Chi Hsu, Anne U. Jackson, Mika Kähönen, Anuradhani Kasturiratne, Brigitte Kühnel, Karin Leander, Wen-Jane Lee, Keng-Hung Lin, Jian ’an Luan, Colin A. McKenzie, He Meian, Christopher P. Nelson, Rainer Rauramaa, Nicole Schupf, Robert A. Scott, Wayne H.H. Sheu, Alena Stančáková, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Heming Wang, Yajuan Wang, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Tamuno Alfred, Najaf Amin, Dan Arking, Tin Aung, R. Graham Barr, Lawrence F. Bielak, Eric Boerwinkle, Erwin P. Bottinger, Peter S. Braund, Jennifer A. Brody, Ulrich Broeckel, Claudia P. Cabrera, Brian Cade, Yu Caizheng, Archie Campbell, Mickaël Canouil, Aravinda Chakravarti, Ganesh Chauhan, Kaare Christensen, Massimiliano Cocca, Francis S. Collins, John M. Connell, Renée de Mutsert, H. Janaka de Silva, Stephanie Debette, Marcus Dörr, Qing Duan, Charles B. Eaton, Georg Ehret, Evangelos Evangelou, Jessica D. Faul, Virginia A. Fisher, Nita G. Forouhi, Oscar H. Franco, Yechiel Friedlander, He Gao, Bruna Gigante, Misa Graff, C. Charles Gu, Dongfeng Gu, Preeti Gupta, Saskia P. Hagenaars, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Albert Hofman, Barbara V. Howard, Steven Hunt, Marguerite R. Irvin, Yucheng Jia, Roby Joehanes, Anne E. Justice, Tomohiro Katsuya, Joel Kaufman, Nicola D. Kerrison, Chiea Chuen Khor, Woon-Puay Koh, Heikki A. Koistinen, Pirjo Komulainen, Charles Kooperberg, Jose E. Krieger, Michiaki Kubo, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Benjamin Lehne, Cora E. Lewis, Yize Li, Sing Hui Lim, Shiow Lin, Ching-Ti Liu, Jianjun Liu, Jingmin Liu, Kiang Liu, Yeheng Liu, Marie Loh, Kurt K. Lohman, Jirong Long, Tin Louie, Reedik Mägi, Anubha Mahajan, Thomas Meitinger, Andres Metspalu, Lili Milani, Yukihide Momozawa, Andrew P. Morris, Thomas H. Mosley, Peter Munson, Alison D. Murray, Mike A. Nalls, Ubaydah Nasri, Jill M. Norris, Kari North, Adesola Ogunniyi, Sandosh Padmanabhan, Walter R. Palmas, Nicholette D. Palmer, James S. Pankow, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, Olli T. Raitakari, Frida Renström, Treva K. Rice, Paul M. Ridker, Antonietta Robino, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Charumathi Sabanayagam, Babatunde L. Salako, Kevin Sandow, Carsten O. Schmidt, Pamela J. Schreiner, William R. Scott, Sudha Seshadri, Peter Sever, Colleen M. Sitlani, Jennifer A. Smith, Harold Snieder, John M. Starr, Konstantin Strauch, Hua Tang, Kent D. Taylor, Yik Ying Teo, Yih Chung Tham, André G. Uitterlinden, Melanie Waldenberger, Lihua Wang, Ya X. Wang, Wen Bin Wei, Christine Williams, Gregory Wilson, Mary K. Wojczynski, Jie Yao, Jian-Min Yuan, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, John C. Chambers, Yii-Der Ida Chen, Ulf de Faire, Ian J. Deary, Tõnu Esko, Martin Farrall, Terrence Forrester, Paul W. Franks, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Bernardo Lessa Horta, Yi-Jen Hung, Jost B. Jonas, Norihiro Kato, Jaspal S. Kooner, Markku Laakso, Terho Lehtimäki, Kae-Woei Liang, Patrik K.E. Magnusson, Anne B. Newman, Albertine J. Oldehinkel, Alexandre C. Pereira, Susan Redline, Rainer Rettig, Nilesh J. Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E. Wagenknecht, Nicholas J. Wareham, Hugh Watkins, David R. Weir, Ananda R. Wickremasinghe, Tangchun Wu, Wei Zheng, Yoichiro Kamatani, Cathy C. Laurie, Claude Bouchard, Richard S. Cooper, Michele K. Evans, Vilmundur Gudnason, Sharon L.R. Kardia, Stephen B. Kritchevsky, Daniel Levy, Jeff R. O’Connell, Bruce M. Psaty, Rob M. van Dam, Mario Sims, Donna K. Arnett, Dennis O. Mook-Kanamori, Tanika N. Kelly, Ervin R. Fox, Caroline Hayward, Myriam Fornage, Charles N. Rotimi, Michael A. Province, Cornelia M. van Duijn, E. Shyong Tai, Tien Yin Wong, Ruth J.F. Loos, Alex P. Reiner, Jerome I. Rotter, Xiaofeng Zhu, Laura J. Bierut, W. James Gauderman, Mark J. Caulfield, Paul Elliott, Kenneth Rice, Patricia B. Munroe, Alanna C. Morrison, L. Adrienne Cupples, Dabeeru C. Rao, Daniel I. Chasman
      Genome-wide associa...
      PubDate: 2018-02-26T09:16:27Z
  • Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar
           Proteinosis with Hypogammaglobulinemia
    • Authors: Kazutoshi Cho; Masafumi Yamada; Kazunaga Agematsu; Hirokazu Kanegane; Noriko Miyake; Masahiro Ueki; Takuma Akimoto; Norimoto Kobayashi; Satoru Ikemoto; Mishie Tanino; Atsushi Fujita; Itaru Hayasaka; Satoshi Miyamoto; Mari Tanaka-Kubota; Koh Nakata; Masaaki Shiina; Kazuhiro Ogata; Hisanori Minakami; Naomichi Matsumoto; Tadashi Ariga
      Abstract: Publication date: Available online 15 February 2018
      Source:The American Journal of Human Genetics
      Author(s): Kazutoshi Cho, Masafumi Yamada, Kazunaga Agematsu, Hirokazu Kanegane, Noriko Miyake, Masahiro Ueki, Takuma Akimoto, Norimoto Kobayashi, Satoru Ikemoto, Mishie Tanino, Atsushi Fujita, Itaru Hayasaka, Satoshi Miyamoto, Mari Tanaka-Kubota, Koh Nakata, Masaaki Shiina, Kazuhiro Ogata, Hisanori Minakami, Naomichi Matsumoto, Tadashi Ariga
      Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,′5′-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother’s peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs.

      PubDate: 2018-02-26T09:16:27Z
      DOI: 10.1016/j.ajhg.2018.01.019
  • Assessment of the Clinical Relevance of BRCA2 Missense Variants by
           Functional and Computational Approaches
    • Authors: Lucia Guidugli; Hermela Shimelis; David L. Masica; Vernon S. Pankratz; Gary B. Lipton; Namit Singh; Chunling Hu; Alvaro N.A. Monteiro; Noralane M. Lindor; David E. Goldgar; Rachel Karchin; Edwin S. Iversen; Fergus J. Couch
      Abstract: Publication date: Available online 25 January 2018
      Source:The American Journal of Human Genetics
      Author(s): Lucia Guidugli, Hermela Shimelis, David L. Masica, Vernon S. Pankratz, Gary B. Lipton, Namit Singh, Chunling Hu, Alvaro N.A. Monteiro, Noralane M. Lindor, David E. Goldgar, Rachel Karchin, Edwin S. Iversen, Fergus J. Couch
      Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ≥99% probability of pathogenicity, and 73 had ≥95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequence-based prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly (p < 0.05) over-predicted pathogenic variants. We subsequently combined functional and Align-GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the overall probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, we used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay. Together, the results show that systematic functional assays in combination with in silico predictors of pathogenicity provide robust tools for clinical annotation of BRCA2 VUS.

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

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

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

      PubDate: 2018-01-26T06:58:25Z
      DOI: 10.1016/j.ajhg.2017.12.012
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