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Publisher: Elsevier   (Total: 3030 journals)

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Showing 1 - 200 of 3030 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 303, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription  
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 196, 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: 9, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 120, 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: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 24, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 24, 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: 8, 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: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 38, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 33, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, 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: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 5, 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: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, 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: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 304, 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: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 390, 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: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 48, 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: 3, 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: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 7, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, 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: 174, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
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: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 154, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 143, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Human Genetics
  [SJR: 8.769]   [H-I: 256]   [32 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3030 journals]
  • 2016 Presidential Address: Let’s Make Human Genetics Great (Again): The
           Importance of Beauty in Science1
    • Authors: Harry C. Dietz
      Pages: 379 - 384
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Harry C. Dietz

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.009
  • 2016 William Allan Award Introduction: James Gusella1
    • Authors: David L. Nelson
      Pages: 385 - 386
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): David L. Nelson

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.016
  • 2016 William Allan Award: Human Disease Research: Genetic Cycling and
    • Authors: James F. Gusella
      Pages: 387 - 394
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): James F. Gusella

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.008
  • 2016 Curt Stern Award Introduction: Brendan Lee1
    • Authors: Arthur L. Beaudet
      Pages: 395 - 396
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Arthur L. Beaudet

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.007
  • 2016 Curt Stern Award Address: From Rare to Common Diseases: Translating
           Genetic Discovery to Therapy1
    • Authors: Brendan Lee
      Pages: 397 - 400
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Brendan Lee

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.02.001
  • 2016 Victor A. McKusick Leadership Award Introduction: Stanley Gartler1
    • Authors: Gail P. Jarvik
      Pages: 401 - 402
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Gail P. Jarvik

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.012
  • 2016 Victor A. McKusick Leadership Award1
    • Authors: Gail P. Jarvik
      Pages: 401 - 402
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Stanley M. Gartler

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.012
  • Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits
    • Authors: Mete Civelek; Ying Wu; Calvin Pan; Chelsea K. Raulerson; Arthur Ko; Aiqing He; Charles Tilford; Niyas K. Saleem; Alena Stančáková; Laura J. Scott; Christian Fuchsberger; Heather M. Stringham; Anne U. Jackson; Narisu Narisu; Peter S. Chines; Kerrin S. Small; Johanna Kuusisto; Brian W. Parks; Päivi Pajukanta; Todd Kirchgessner; Francis S. Collins; Peter S. Gargalovic; Michael Boehnke; Markku Laakso; Karen L. Mohlke; Aldons J. Lusis
      Pages: 428 - 443
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Mete Civelek, Ying Wu, Calvin Pan, Chelsea K. Raulerson, Arthur Ko, Aiqing He, Charles Tilford, Niyas K. Saleem, Alena Stančáková, Laura J. Scott, Christian Fuchsberger, Heather M. Stringham, Anne U. Jackson, Narisu Narisu, Peter S. Chines, Kerrin S. Small, Johanna Kuusisto, Brian W. Parks, Päivi Pajukanta, Todd Kirchgessner, Francis S. Collins, Peter S. Gargalovic, Michael Boehnke, Markku Laakso, Karen L. Mohlke, Aldons J. Lusis
      Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10−8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.027
  • Integrating Gene Expression with Summary Association Statistics to
           Identify Genes Associated with 30 Complex Traits
    • Authors: Nicholas Mancuso; Huwenbo Shi; Pagé Goddard; Gleb Kichaev; Alexander Gusev; Bogdan Pasaniuc
      Pages: 473 - 487
      Abstract: Publication date: Available online 23 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Nicholas Mancuso, Huwenbo Shi, Pagé Goddard, Gleb Kichaev, Alexander Gusev, Bogdan Pasaniuc
      Although genome-wide association studies (GWASs) have identified thousands of risk loci for many complex traits and diseases, the causal variants and genes at these loci remain largely unknown. Here, we introduce a method for estimating the local genetic correlation between gene expression and a complex trait and utilize it to estimate the genetic correlation due to predicted expression between pairs of traits. We integrated gene expression measurements from 45 expression panels with summary GWAS data to perform 30 multi-tissue transcriptome-wide association studies (TWASs). We identified 1,196 genes whose expression is associated with these traits; of these, 168 reside more than 0.5 Mb away from any previously reported GWAS significant variant. We then used our approach to find 43 pairs of traits with significant genetic correlation at the level of predicted expression; of these, eight were not found through genetic correlation at the SNP level. Finally, we used bi-directional regression to find evidence that BMI causally influences triglyceride levels and that triglyceride levels causally influence low-density lipoprotein. Together, our results provide insight into the role of gene expression in the susceptibility of complex traits and diseases.

      PubDate: 2017-03-02T15:40:24Z
      DOI: 10.1016/j.ajhg.2017.01.031
  • CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased
           Transmission of Congenital Myotonic Dystrophy
    • Authors: Lise Barbé; Stella Lanni; Arturo López-Castel; Silvie Franck; Claudia Spits; Kathelijn Keymolen; Sara Seneca; Stephanie Tomé; Ioana Miron; Julie Letourneau; Minggao Liang; Sanaa Choufani; Rosanna Weksberg; Michael D. Wilson; Zdenek Sedlacek; Cynthia Gagnon; Zuzana Musova; David Chitayat; Patrick Shannon; Jean Mathieu; Karen Sermon; Christopher E. Pearson
      Pages: 488 - 505
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Lise Barbé, Stella Lanni, Arturo López-Castel, Silvie Franck, Claudia Spits, Kathelijn Keymolen, Sara Seneca, Stephanie Tomé, Ioana Miron, Julie Letourneau, Minggao Liang, Sanaa Choufani, Rosanna Weksberg, Michael D. Wilson, Zdenek Sedlacek, Cynthia Gagnon, Zuzana Musova, David Chitayat, Patrick Shannon, Jean Mathieu, Karen Sermon, Christopher E. Pearson
      CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10−12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.033
  • A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human
    • Authors: Nahuel A. Paolini; Martin Attwood; Samuel B. Sondalle; Carolina Marques dos Santos Vieira; Anita M. van Adrichem; Franca M. di Summa; Marie-Françoise O’Donohue; Pierre-Emmanuel Gleizes; Swaksha Rachuri; Joseph W. Briggs; Roman Fischer; Peter J. Ratcliffe; Marcin W. Wlodarski; Riekelt H. Houtkooper; Marieke von Lindern; Taco W. Kuijpers; Jonathan D. Dinman; Susan J. Baserga; Matthew E. Cockman; Alyson W. MacInnes
      Pages: 506 - 522
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Nahuel A. Paolini, Martin Attwood, Samuel B. Sondalle, Carolina Marques dos Santos Vieira, Anita M. van Adrichem, Franca M. di Summa, Marie-Françoise O’Donohue, Pierre-Emmanuel Gleizes, Swaksha Rachuri, Joseph W. Briggs, Roman Fischer, Peter J. Ratcliffe, Marcin W. Wlodarski, Riekelt H. Houtkooper, Marieke von Lindern, Taco W. Kuijpers, Jonathan D. Dinman, Susan J. Baserga, Matthew E. Cockman, Alyson W. MacInnes
      Ribosomal protein (RP) gene mutations, mostly associated with inherited or acquired bone marrow failure, are believed to drive disease by slowing the rate of protein synthesis. Here de novo missense mutations in the RPS23 gene, which codes for uS12, are reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features. One individual additionally presents with intellectual disability and autism spectrum disorder. The amino acid substitutions lie in two highly conserved loop regions of uS12 with known roles in maintaining the accuracy of mRNA codon translation. Primary cells revealed one substitution severely impaired OGFOD1-dependent hydroxylation of a neighboring proline residue resulting in 40S ribosomal subunits that were blocked from polysome formation. The other disrupted a predicted pi-pi stacking interaction between two phenylalanine residues leading to a destabilized uS12 that was poorly tolerated in 40S subunit biogenesis. Despite no evidence of a reduction in the rate of mRNA translation, these uS12 variants impaired the accuracy of mRNA translation and rendered cells highly sensitive to oxidative stress. These discoveries describe a ribosomopathy linked to uS12 and reveal mechanistic distinctions between RP gene mutations driving hematopoietic disease and those resulting in developmental disorders.

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.034
  • Hypomorphic Pathogenic Variants in TAF13 Are Associated with
           Autosomal-Recessive Intellectual Disability and Microcephaly
    • Authors: Hasan Tawamie; Igor Martianov; Natalie Wohlfahrt; Rebecca Buchert; Gabrielle Mengus; Steffen Uebe; Luigi Janiri; Franz Wolfgang Hirsch; Johannes Schumacher; Fulvia Ferrazzi; Heinrich Sticht; André Reis; Irwin Davidson; Roberto Colombo; Rami Abou Jamra
      Pages: 555 - 561
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Hasan Tawamie, Igor Martianov, Natalie Wohlfahrt, Rebecca Buchert, Gabrielle Mengus, Steffen Uebe, Luigi Janiri, Franz Wolfgang Hirsch, Johannes Schumacher, Fulvia Ferrazzi, Heinrich Sticht, André Reis, Irwin Davidson, Roberto Colombo, Rami Abou Jamra
      In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.032
  • Thyroglobulin in Metastatic Thyroid Cancer: Culprit or Red Herring?
    • Authors: Lamis Yehia; Ying Ni; Charis Eng
      Pages: 562 - 563
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Lamis Yehia, Ying Ni, Charis Eng

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.023
  • Response to Yehia et al.
    • Authors: Abdul K. Siraj; Tariq Masoodi; Fowzan S. Alkuraya; Khawla S. Al-Kuraya
      Pages: 564 - 565
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Abdul K. Siraj, Tariq Masoodi, Fowzan S. Alkuraya, Khawla S. Al-Kuraya

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.022
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 181 - 182
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2016.12.007
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 181 - 182
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2016.12.007
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 183 - 184
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Kathryn B. Garber

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2017.01.015
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 183 - 184
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Kathryn B. Garber

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.015
  • The Undiagnosed Diseases Network: Accelerating Discovery about Health and
    • Authors: Rachel B. Ramoni; John J. Mulvihill; David R. Adams; Patrick Allard; Euan A. Ashley; Jonathan A. Bernstein; William A. Gahl; Rizwan Hamid; Joseph Loscalzo; Alexa T. McCray; Vandana Shashi; Cynthia J. Tifft; Anastasia L. Wise
      Pages: 185 - 192
      Abstract: Publication date: 2 February 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 2
      Author(s): Rachel B. Ramoni, John J. Mulvihill, David R. Adams, Patrick Allard, Euan A. Ashley, Jonathan A. Bernstein, William A. Gahl, Rizwan Hamid, Joseph Loscalzo, Alexa T. McCray, Vandana Shashi, Cynthia J. Tifft, Anastasia L. Wise
      Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

      PubDate: 2017-02-03T13:51:08Z
      DOI: 10.1016/j.ajhg.2017.01.006
  • De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a
           Syndromic Neurodevelopmental Disorder
    • Authors: Sébastien Küry; Thomas Besnard; Frédéric Ebstein; Tahir N. Khan; Tomasz Gambin; Jessica Douglas; Carlos A. Bacino; William J. Craigen; Stephan J. Sanders; Andrea Lehmann; Xénia Latypova; Kamal Khan; Mathilde Pacault; Stephanie Sacharow; Kimberly Glaser; Eric Bieth; Laurence Perrin-Sabourin; Marie-Line Jacquemont; Megan T. Cho; Elizabeth Roeder; Anne-Sophie Denommé-Pichon; Kristin G. Monaghan; Bo Yuan; Fan Xia; Sylvain Simon; Dominique Bonneau; Philippe Parent; Brigitte Gilbert-Dussardier; Sylvie Odent; Annick Toutain; Laurent Pasquier; Deborah Barbouth; Chad A. Shaw; Ankita Patel; Janice L. Smith; Weimin Bi; Sébastien Schmitt; Wallid Deb; Mathilde Nizon; Sandra Mercier; Marie Vincent; Caroline Rooryck; Valérie Malan; Ignacio Briceño; Alberto Gómez; Kimberly M. Nugent; James B. Gibson; Benjamin Cogné; James R. Lupski; Holly A.F. Stessman; Evan E. Eichler; Kyle Retterer; Yaping Yang; Richard Redon; Nicholas Katsanis; Jill A. Rosenfeld; Peter-Michael Kloetzel; Christelle Golzio; Stéphane Bézieau; Paweł Stankiewicz; Bertrand Isidor
      Pages: 352 - 363
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, Jessica Douglas, Carlos A. Bacino, William J. Craigen, Stephan J. Sanders, Andrea Lehmann, Xénia Latypova, Kamal Khan, Mathilde Pacault, Stephanie Sacharow, Kimberly Glaser, Eric Bieth, Laurence Perrin-Sabourin, Marie-Line Jacquemont, Megan T. Cho, Elizabeth Roeder, Anne-Sophie Denommé-Pichon, Kristin G. Monaghan, Bo Yuan, Fan Xia, Sylvain Simon, Dominique Bonneau, Philippe Parent, Brigitte Gilbert-Dussardier, Sylvie Odent, Annick Toutain, Laurent Pasquier, Deborah Barbouth, Chad A. Shaw, Ankita Patel, Janice L. Smith, Weimin Bi, Sébastien Schmitt, Wallid Deb, Mathilde Nizon, Sandra Mercier, Marie Vincent, Caroline Rooryck, Valérie Malan, Ignacio Briceño, Alberto Gómez, Kimberly M. Nugent, James B. Gibson, Benjamin Cogné, James R. Lupski, Holly A.F. Stessman, Evan E. Eichler, Kyle Retterer, Yaping Yang, Richard Redon, Nicholas Katsanis, Jill A. Rosenfeld, Peter-Michael Kloetzel, Christelle Golzio, Stéphane Bézieau, Paweł Stankiewicz, Bertrand Isidor

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2017.01.003
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 1 - 2
      Abstract: Publication date: 2 February 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 2
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-02-03T13:51:08Z
      DOI: 10.1016/j.ajhg.2016.12.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 3 - 4
      Abstract: Publication date: 2 February 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 2
      Author(s): Kathryn B. Garber

      PubDate: 2017-02-03T13:51:08Z
      DOI: 10.1016/j.ajhg.2016.12.005
  • Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals
           with Intellectual Disability and Epilepsy
    • Authors: Myriam Srour; Noriaki Shimokawa; Fadi F. Hamdan; Christina Nassif; Chantal Poulin; Lihadh Al Gazali; Jill A. Rosenfeld; Noriyuki Koibuchi; Guy A. Rouleau; Aisha Al Shamsi; Jacques L. Michaud
      Abstract: Publication date: Available online 20 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Myriam Srour, Noriaki Shimokawa, Fadi F. Hamdan, Christina Nassif, Chantal Poulin, Lihadh Al Gazali, Jill A. Rosenfeld, Noriyuki Koibuchi, Guy A. Rouleau, Aisha Al Shamsi, Jacques L. Michaud
      Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.

      PubDate: 2017-04-25T01:33:29Z
      DOI: 10.1016/j.ajhg.2017.03.009
  • PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by
           Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic
    • Authors: Emma A. Hall; Michael S. Nahorski; Lyndsay M. Murray; Ranad Shaheen; Emma Perkins; Kosala N. Dissanayake; Yosua Kristaryanto; Ross A. Jones; Julie Vogt; Manon Rivagorda; Mark T. Handley; Girish R. Mali; Tooba Quidwai; Dinesh C. Soares; Margaret A. Keighren; Lisa McKie; Richard L. Mort; Noor Gammoh; Amaya Garcia-Munoz; Tracey Davey; Matthieu Vermeren; Diana Walsh; Peter Budd; Irene A. Aligianis; Eissa Faqeih; Alan J. Quigley; Ian J. Jackson; Yogesh Kulathu; Mandy Jackson; Richard R. Ribchester; Alex von Kriegsheim; Fowzan S. Alkuraya; C. Geoffrey Woods; Eamonn R. Maher; Pleasantine Mill
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Emma A. Hall, Michael S. Nahorski, Lyndsay M. Murray, Ranad Shaheen, Emma Perkins, Kosala N. Dissanayake, Yosua Kristaryanto, Ross A. Jones, Julie Vogt, Manon Rivagorda, Mark T. Handley, Girish R. Mali, Tooba Quidwai, Dinesh C. Soares, Margaret A. Keighren, Lisa McKie, Richard L. Mort, Noor Gammoh, Amaya Garcia-Munoz, Tracey Davey, Matthieu Vermeren, Diana Walsh, Peter Budd, Irene A. Aligianis, Eissa Faqeih, Alan J. Quigley, Ian J. Jackson, Yogesh Kulathu, Mandy Jackson, Richard R. Ribchester, Alex von Kriegsheim, Fowzan S. Alkuraya, C. Geoffrey Woods, Eamonn R. Maher, Pleasantine Mill
      During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.

      PubDate: 2017-04-18T01:12:23Z
      DOI: 10.1016/j.ajhg.2017.03.008
  • Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated
           with Both Familial and Sporadic Pituitary Adenomas
    • Authors: Qilin Zhang; Cheng Peng; Jianping Song; Yichao Zhang; Jianhua Chen; Zhijian Song; Xuefei Shou; Zengyi Ma; Hong Peng; Xuemin Jian; Wenqiang He; Zhao Ye; Zhiqiang Li; Yongfei Wang; Hongying Ye; Zhaoyun Zhang; Ming Shen; Feng Tang; Hong Chen; Zhifeng Shi; Chunjui Chen; Zhengyuan Chen; Yue Shen; Ye Wang; Shaoyong Lu; Jian Zhang; Yiming Li; Shiqi Li; Ying Mao; Liangfu Zhou; Hai Yan; Yongyong Shi; Chuanxin Huang; Yao Zhao
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Qilin Zhang, Cheng Peng, Jianping Song, Yichao Zhang, Jianhua Chen, Zhijian Song, Xuefei Shou, Zengyi Ma, Hong Peng, Xuemin Jian, Wenqiang He, Zhao Ye, Zhiqiang Li, Yongfei Wang, Hongying Ye, Zhaoyun Zhang, Ming Shen, Feng Tang, Hong Chen, Zhifeng Shi, Chunjui Chen, Zhengyuan Chen, Yue Shen, Ye Wang, Shaoyong Lu, Jian Zhang, Yiming Li, Shiqi Li, Ying Mao, Liangfu Zhou, Hai Yan, Yongyong Shi, Chuanxin Huang, Yao Zhao
      Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10−7). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.

      PubDate: 2017-04-18T01:12:23Z
      DOI: 10.1016/j.ajhg.2017.03.011
  • Human Demographic History Impacts Genetic Risk Prediction across Diverse
    • Authors: Alicia R. Martin; Christopher R. Gignoux; Raymond K. Walters; Genevieve L. Wojcik; Benjamin M. Neale; Simon Gravel; Mark J. Daly; Carlos D. Bustamante; Eimear E. Kenny
      Abstract: Publication date: Available online 30 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Alicia R. Martin, Christopher R. Gignoux, Raymond K. Walters, Genevieve L. Wojcik, Benjamin M. Neale, Simon Gravel, Mark J. Daly, Carlos D. Bustamante, Eimear E. Kenny
      The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics.

      PubDate: 2017-04-04T00:28:01Z
      DOI: 10.1016/j.ajhg.2017.03.004
  • Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher
           Disease with Human iPSC-Derived Oligodendrocytes
    • Authors: Zachary S. Nevin; Daniel C. Factor; Robert T. Karl; Panagiotis Douvaras; Jeremy Laukka; Martha S. Windrem; Steven A. Goldman; Valentina Fossati; Grace M. Hobson; Paul J. Tesar
      Abstract: Publication date: Available online 30 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Zachary S. Nevin, Daniel C. Factor, Robert T. Karl, Panagiotis Douvaras, Jeremy Laukka, Martha S. Windrem, Steven A. Goldman, Valentina Fossati, Grace M. Hobson, Paul J. Tesar
      Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD—including point mutations and duplication, triplication, and deletion of PLP1—and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

      PubDate: 2017-04-04T00:28:01Z
      DOI: 10.1016/j.ajhg.2017.03.005
  • Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome
           Associated with Seizures and Dysmorphic Features
    • Authors: Teresa Santiago-Sim; Lindsay C. Burrage; Frédéric Ebstein; Mari J. Tokita; Marcus Miller; Weimin Bi; Alicia A. Braxton; Jill A. Rosenfeld; Maher Shahrour; Andrea Lehmann; Benjamin Cogné; Sébastien Küry; Thomas Besnard; Bertrand Isidor; Stéphane Bézieau; Isabelle Hazart; Honey Nagakura; LaDonna L. Immken; Rebecca O. Littlejohn; Elizabeth Roeder; Bulent Kara; Katia Hardies; Sarah Weckhuysen; Patrick May; Johannes R. Lemke; Orly Elpeleg; Bassam Abu-Libdeh; Kiely N. James; Jennifer L. Silhavy; Mahmoud Y. Issa; Maha S. Zaki; Joseph G. Gleeson; John R. Seavitt; Mary E. Dickinson; M. Cecilia Ljungberg; Sara Wells; Sara J. Johnson; Lydia Teboul; Christine M. Eng; Yaping Yang; Peter-Michael Kloetzel; Jason D. Heaney; Magdalena A. Walkiewicz; Zaid Afawi; Rudi Balling; Nina Barisic; Stéphanie Baulac; Dana Craiu; Peter De Jonghe; Rosa Guerrero-Lopez; Renzo Guerrini; Ingo Helbig; Helle Hjalgrim; Johanna Jähn; Karl Martin Klein; Eric Leguern; Holger Lerche; Carla Marini; Hiltrud Muhle; Felix Rosenow; José Serratosa; Katalin Sterbová; Arvid Suls; Rikke S. Moller; Pasquale Striano; Yvonne Weber; Federico Zara
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Teresa Santiago-Sim, Lindsay C. Burrage, Frédéric Ebstein, Mari J. Tokita, Marcus Miller, Weimin Bi, Alicia A. Braxton, Jill A. Rosenfeld, Maher Shahrour, Andrea Lehmann, Benjamin Cogné, Sébastien Küry, Thomas Besnard, Bertrand Isidor, Stéphane Bézieau, Isabelle Hazart, Honey Nagakura, LaDonna L. Immken, Rebecca O. Littlejohn, Elizabeth Roeder, Bulent Kara, Katia Hardies, Sarah Weckhuysen, Patrick May, Johannes R. Lemke, Orly Elpeleg, Bassam Abu-Libdeh, Kiely N. James, Jennifer L. Silhavy, Mahmoud Y. Issa, Maha S. Zaki, Joseph G. Gleeson, John R. Seavitt, Mary E. Dickinson, M. Cecilia Ljungberg, Sara Wells, Sara J. Johnson, Lydia Teboul, Christine M. Eng, Yaping Yang, Peter-Michael Kloetzel, Jason D. Heaney, Magdalena A. Walkiewicz
      Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.03.001
  • Functional Architectures of Local and Distal Regulation of Gene Expression
           in Multiple Human Tissues
    • Authors: Xuanyao Liu; Hilary K. Finucane; Alexander Gusev; Gaurav Bhatia; Steven Gazal; Luke O’Connor; Brendan Bulik-Sullivan; Fred A. Wright; Patrick F. Sullivan; Benjamin M. Neale; Alkes L. Price
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Xuanyao Liu, Hilary K. Finucane, Alexander Gusev, Gaurav Bhatia, Steven Gazal, Luke O’Connor, Brendan Bulik-Sullivan, Fred A. Wright, Patrick F. Sullivan, Benjamin M. Neale, Alkes L. Price
      Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.41×), conserved regions (4.67×), and four histone marks (p < 5 × 10−5 for all enrichments); local enrichments were similar across the 15 tissues. We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.47×), conserved regions (4.51×), and two histone marks (p < 3 × 10−7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.03.002
  • De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D
           Cause an Intellectual Disability Syndrome
    • Authors: Sandra Jansen; Sinje Geuer; Rolph Pfundt; Rachel Brough; Priyanka Ghongane; Johanna C. Herkert; Elysa J. Marco; Marjolein H. Willemsen; Tjitske Kleefstra; Mark Hannibal; Joseph T. Shieh; Sally Ann Lynch; Frances Flinter; David R. FitzPatrick; Alice Gardham; Birgitta Bernhard; Nicola Ragge; Ruth Newbury-Ecob; Raphael Bernier; Malin Kvarnung; E.A. Helena Magnusson; Marja W. Wessels; Marjon A. van Slegtenhorst; Kristin G. Monaghan; Petra de Vries; Joris A. Veltman; Christopher J. Lord; Lisenka E.L.M. Vissers; Bert B.A. de Vries
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Sandra Jansen, Sinje Geuer, Rolph Pfundt, Rachel Brough, Priyanka Ghongane, Johanna C. Herkert, Elysa J. Marco, Marjolein H. Willemsen, Tjitske Kleefstra, Mark Hannibal, Joseph T. Shieh, Sally Ann Lynch, Frances Flinter, David R. FitzPatrick, Alice Gardham, Birgitta Bernhard, Nicola Ragge, Ruth Newbury-Ecob, Raphael Bernier, Malin Kvarnung, E.A. Helena Magnusson, Marja W. Wessels, Marjon A. van Slegtenhorst, Kristin G. Monaghan, Petra de Vries, Joris A. Veltman, Christopher J. Lord, Lisenka E.L.M. Vissers, Bert B.A. de Vries
      Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%–40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.005
  • Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann
           Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita
    • Authors: Shifeng Xue; Jérôme Maluenda; Florent Marguet; Mohammad Shboul; Loïc Quevarec; Carine Bonnard; Alvin Yu Jin Ng; Sumanty Tohari; Thong Teck Tan; Mung Kei Kong; Kristin G. Monaghan; Megan T. Cho; Carly E. Siskind; Jacinda B. Sampson; Carolina Tesi Rocha; Fawaz Alkazaleh; Marie Gonzales; Luc Rigonnot; Sandra Whalen; Marta Gut; Ivo Gut; Martine Bucourt; Byrappa Venkatesh; Annie Laquerrière; Bruno Reversade; Judith Melki
      Abstract: Publication date: Available online 16 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Shifeng Xue, Jérôme Maluenda, Florent Marguet, Mohammad Shboul, Loïc Quevarec, Carine Bonnard, Alvin Yu Jin Ng, Sumanty Tohari, Thong Teck Tan, Mung Kei Kong, Kristin G. Monaghan, Megan T. Cho, Carly E. Siskind, Jacinda B. Sampson, Carolina Tesi Rocha, Fawaz Alkazaleh, Marie Gonzales, Luc Rigonnot, Sandra Whalen, Marta Gut, Ivo Gut, Martine Bucourt, Byrappa Venkatesh, Annie Laquerrière, Bruno Reversade, Judith Melki
      Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.006
  • Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and
           Renal Syndrome
    • Authors: Asaf Ta-Shma; Tahir N. Khan; Asaf Vivante; Jason R. Willer; Pavle Matak; Chaim Jalas; Ben Pode-Shakked; Yishay Salem; Yair Anikster; Friedhelm Hildebrandt; Nicholas Katsanis; Orly Elpeleg; Erica E. Davis
      Abstract: Publication date: Available online 16 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R. Willer, Pavle Matak, Chaim Jalas, Ben Pode-Shakked, Yishay Salem, Yair Anikster, Friedhelm Hildebrandt, Nicholas Katsanis, Orly Elpeleg, Erica E. Davis
      Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.007
  • Large-Scale trans-eQTLs Affect Hundreds of Transcripts and Mediate
           Patterns of Transcriptional Co-regulation
    • Authors: Boel Brynedal; JinMyung Choi; Towfique Raj; Robert Bjornson; Barbara E. Stranger; Benjamin M. Neale; Benjamin F. Voight; Chris Cotsapas
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Boel Brynedal, JinMyung Choi, Towfique Raj, Robert Bjornson, Barbara E. Stranger, Benjamin M. Neale, Benjamin F. Voight, Chris Cotsapas
      Efforts to decipher the causal relationships between differences in gene regulation and corresponding differences in phenotype have been stymied by several basic technical challenges. Although detecting local, cis-eQTLs is now routine, trans-eQTLs, which are distant from the genes of origin, are far more difficult to find because millions of SNPs must currently be compared to thousands of transcripts. Here, we demonstrate an alternative approach: we looked for SNPs associated with the expression of many genes simultaneously and found that hundreds of trans-eQTLs each affect hundreds of transcripts in lymphoblastoid cell lines across three African populations. These trans-eQTLs target the same genes across the three populations and show the same direction of effect. We discovered that target transcripts of a high-confidence set of trans-eQTLs encode proteins that interact more frequently than expected by chance, are bound by the same transcription factors, and are enriched for pathway annotations indicative of roles in basic cell homeostasis. We thus demonstrate that our approach can uncover trans-acting transcriptional control circuits that affect co-regulated groups of genes: a key to understanding how cellular pathways and processes are orchestrated.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.004
  • Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration
           with or without Additional Developmental Anomalies
    • Authors: Mingchu Xu; Yajing (Angela) Xie; Hana Abouzeid; Christopher T. Gordon; Alessia Fiorentino; Zixi Sun; Anna Lehman; Ihab S. Osman; Rachayata Dharmat; Rosa Riveiro-Alvarez; Linda Bapst-Wicht; Darwin Babino; Gavin Arno; Virginia Busetto; Li Zhao; Hui Li; Miguel A. Lopez-Martinez; Liliana F. Azevedo; Laurence Hubert; Nikolas Pontikos; Aiden Eblimit; Isabel Lorda-Sanchez; Valeria Kheir; Vincent Plagnol; Myriam Oufadem; Zachry T. Soens; Lizhu Yang; Christine Bole-Feysot; Rolph Pfundt; Nathalie Allaman-Pillet; Patrick Nitschké; Michael E. Cheetham; Stanislas Lyonnet; Smriti A. Agrawal; Huajin Li; Gaëtan Pinton; Michel Michaelides; Claude Besmond; Yumei Li; Zhisheng Yuan; Johannes von Lintig; Andrew R. Webster; Hervé Le Hir; Peter Stoilov; Jeanne Amiel; Alison J. Hardcastle; Carmen Ayuso; Ruifang Sui; Rui Chen; Rando Allikmets; Daniel F. Schorderet; Graeme Black; Georgina Hall; Rachel Gillespie; Simon Ramsden; Forbes Manson; Panagiotis Sergouniotis; Chris Inglehearn; Carmel Toomes; Manir Ali; Martin McKibbin; James Poulter; Emma Lord; Andrea Nemeth; Stephanie Halford; Susan Downes; Jing Yu
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Mingchu Xu, Yajing (Angela) Xie, Hana Abouzeid, Christopher T. Gordon, Alessia Fiorentino, Zixi Sun, Anna Lehman, Ihab S. Osman, Rachayata Dharmat, Rosa Riveiro-Alvarez, Linda Bapst-Wicht, Darwin Babino, Gavin Arno, Virginia Busetto, Li Zhao, Hui Li, Miguel A. Lopez-Martinez, Liliana F. Azevedo, Laurence Hubert, Nikolas Pontikos, Aiden Eblimit, Isabel Lorda-Sanchez, Valeria Kheir, Vincent Plagnol, Myriam Oufadem, Zachry T. Soens, Lizhu Yang, Christine Bole-Feysot, Rolph Pfundt, Nathalie Allaman-Pillet, Patrick Nitschké, Michael E. Cheetham, Stanislas Lyonnet, Smriti A. Agrawal, Huajin Li, Gaëtan Pinton, Michel Michaelides, Claude Besmond, Yumei Li, Zhisheng Yuan, Johannes von Lintig, Andrew R. Webster, Hervé Le Hir, Peter Stoilov, Jeanne Amiel, Alison J. Hardcastle, Carmen Ayuso, Ruifang Sui, Rui Chen, Rando Allikmets, Daniel F. Schorderet
      Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.008
  • Dynamic Role of trans Regulation of Gene Expression in Relation to Complex
    • Authors: Chen Yao; Roby Joehanes; Andrew D. Johnson; Tianxiao Huan; Chunyu Liu; Jane E. Freedman; Peter J. Munson; David E. Hill; Marc Vidal; Daniel Levy
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Chen Yao, Roby Joehanes, Andrew D. Johnson, Tianxiao Huan, Chunyu Liu, Jane E. Freedman, Peter J. Munson, David E. Hill, Marc Vidal, Daniel Levy
      Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10−7); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-trans-eGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the trans-eGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.003
  • 2016 ASHG Awards and Addresses
    • Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, 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 given 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: 2017-03-08T16:01:27Z
  • Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
    • Authors: Jae Seok Lim; Ramu Gopalappa; Se Hoon Kim; Suresh Ramakrishna; Minji Lee; Woo-il Kim; Junho Kim; Sang Min Park; Junehawk Lee; Jung-Hwa Oh; Heung Dong Kim; Chang-Hwan Park; Joon Soo Lee; Sangwoo Kim; Dong Seok Kim; Jung Min Han; Hoon-Chul Kang; Hyongbum (Henry) Kim; Jeong Ho Lee
      Abstract: Publication date: Available online 16 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Jae Seok Lim, Ramu Gopalappa, Se Hoon Kim, Suresh Ramakrishna, Minji Lee, Woo-il Kim, Junho Kim, Sang Min Park, Junehawk Lee, Jung-Hwa Oh, Heung Dong Kim, Chang-Hwan Park, Joon Soo Lee, Sangwoo Kim, Dong Seok Kim, Jung Min Han, Hoon-Chul Kang, Hyongbum (Henry) Kim, Jeong Ho Lee
      Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%–25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×–20,012×) of five important mTOR pathway genes—PIK3CA, PIK3R2, AKT3, TSC1, and TSC2—by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

      PubDate: 2017-02-23T14:57:43Z
      DOI: 10.1016/j.ajhg.2017.01.030
  • Public Attitudes toward Consent and Data Sharing in Biobank Research: A
           Large Multi-site Experimental Survey in the US
    • Authors: Saskia C. Sanderson; Kyle B. Brothers; Nathaniel D. Mercaldo; Ellen Wright Clayton; Armand H. Matheny Antommaria; Sharon A. Aufox; Murray H. Brilliant; Diego Campos; David S. Carrell; John Connolly; Pat Conway; Stephanie M. Fullerton; Nanibaa’ A. Garrison; Carol R. Horowitz; Gail P. Jarvik; David Kaufman; Terrie E. Kitchner; Rongling Li; Evette J. Ludman; Catherine A. McCarty; Jennifer B. McCormick; Valerie D. McManus; Melanie F. Myers; Aaron Scrol; Janet L. Williams; Martha J. Shrubsole; Jonathan S. Schildcrout; Maureen E. Smith; Ingrid A. Holm
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Saskia C. Sanderson, Kyle B. Brothers, Nathaniel D. Mercaldo, Ellen Wright Clayton, Armand H. Matheny Antommaria, Sharon A. Aufox, Murray H. Brilliant, Diego Campos, David S. Carrell, John Connolly, Pat Conway, Stephanie M. Fullerton, Nanibaa’ A. Garrison, Carol R. Horowitz, Gail P. Jarvik, David Kaufman, Terrie E. Kitchner, Rongling Li, Evette J. Ludman, Catherine A. McCarty, Jennifer B. McCormick, Valerie D. McManus, Melanie F. Myers, Aaron Scrol, Janet L. Williams, Martha J. Shrubsole, Jonathan S. Schildcrout, Maureen E. Smith, Ingrid A. Holm
      Individuals participating in biobanks and other large research projects are increasingly asked to provide broad consent for open-ended research use and widespread sharing of their biosamples and data. We assessed willingness to participate in a biobank using different consent and data sharing models, hypothesizing that willingness would be higher under more restrictive scenarios. Perceived benefits, concerns, and information needs were also assessed. In this experimental survey, individuals from 11 US healthcare systems in the Electronic Medical Records and Genomics (eMERGE) Network were randomly allocated to one of three hypothetical scenarios: tiered consent and controlled data sharing; broad consent and controlled data sharing; or broad consent and open data sharing. Of 82,328 eligible individuals, exactly 13,000 (15.8%) completed the survey. Overall, 66% (95% CI: 63%–69%) of population-weighted respondents stated they would be willing to participate in a biobank; willingness and attitudes did not differ between respondents in the three scenarios. Willingness to participate was associated with self-identified white race, higher educational attainment, lower religiosity, perceiving more research benefits, fewer concerns, and fewer information needs. Most (86%, CI: 84%–87%) participants would want to know what would happen if a researcher misused their health information; fewer (51%, CI: 47%–55%) would worry about their privacy. The concern that the use of broad consent and open data sharing could adversely affect participant recruitment is not supported by these findings. Addressing potential participants’ concerns and information needs and building trust and relationships with communities may increase acceptance of broad consent and wide data sharing in biobank research.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.021
  • Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause
           Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment
    • Authors: Manuela Wiessner; Andreas Roos; Christopher J. Munn; Ranjith Viswanathan; Tamieka Whyte; Dan Cox; Benedikt Schoser; Caroline Sewry; Helen Roper; Rahul Phadke; Chiara Marini Bettolo; Rita Barresi; Richard Charlton; Carsten G. Bönnemann; Osório Abath Neto; Umbertina C. Reed; Edmar Zanoteli; Cristiane Araújo Martins Moreno; Birgit Ertl-Wagner; Rolf Stucka; Christian De Goede; Tamiris Borges da Silva; Denisa Hathazi; Margherita Dell’Aica; René P. Zahedi; Simone Thiele; Juliane Müller; Helen Kingston; Susanna Müller; Elizabeth Curtis; Maggie C. Walter; Tim M. Strom; Volker Straub; Kate Bushby; Francesco Muntoni; Laura E. Swan; Hanns Lochmüller; Jan Senderek
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Manuela Wiessner, Andreas Roos, Christopher J. Munn, Ranjith Viswanathan, Tamieka Whyte, Dan Cox, Benedikt Schoser, Caroline Sewry, Helen Roper, Rahul Phadke, Chiara Marini Bettolo, Rita Barresi, Richard Charlton, Carsten G. Bönnemann, Osório Abath Neto, Umbertina C. Reed, Edmar Zanoteli, Cristiane Araújo Martins Moreno, Birgit Ertl-Wagner, Rolf Stucka, Christian De Goede, Tamiris Borges da Silva, Denisa Hathazi, Margherita Dell’Aica, René P. Zahedi, Simone Thiele, Juliane Müller, Helen Kingston, Susanna Müller, Elizabeth Curtis, Maggie C. Walter, Tim M. Strom, Volker Straub, Kate Bushby, Francesco Muntoni, Laura E. Swan, Hanns Lochmüller, Jan Senderek
      Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.024
  • Who’s Who' Detecting and Resolving Sample Anomalies in Human DNA
           Sequencing Studies with Peddy
    • Authors: Brent S. Pedersen; Aaron R. Quinlan
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Brent S. Pedersen, Aaron R. Quinlan
      The potential for genetic discovery in human DNA sequencing studies is greatly diminished if DNA samples from a cohort are mislabeled, swapped, or contaminated or if they include unintended individuals. Unfortunately, the potential for such errors is significant since DNA samples are often manipulated by several protocols, labs, or scientists in the process of sequencing. We have developed a software package, peddy, to identify and facilitate the remediation of such errors via interactive visualizations and reports comparing the stated sex, relatedness, and ancestry to what is inferred from the individual genotypes derived from whole-genome (WGS) or whole-exome (WES) sequencing. Peddy predicts a sample’s ancestry using a machine learning model trained on individuals of diverse ancestries from the 1000 Genomes Project reference panel. Peddy facilitates both automated and interactive, visual detection of sample swaps, poor sequencing quality, and other indicators of sample problems that, if left undetected, would inhibit discovery.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.017
  • Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous
    • Authors: Javier A. Couto; August Y. Huang; Dennis J. Konczyk; Jeremy A. Goss; Steven J. Fishman; John B. Mulliken; Matthew L. Warman; Arin K. Greene
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Javier A. Couto, August Y. Huang, Dennis J. Konczyk, Jeremy A. Goss, Steven J. Fishman, John B. Mulliken, Matthew L. Warman, Arin K. Greene
      Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein’s negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.018
  • Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy
           Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy
    • Authors: Daniel P.S. Osborn; Heather L. Pond; Neda Mazaheri; Jeremy Dejardin; Christopher J. Munn; Khaloob Mushref; Edmund S. Cauley; Isabella Moroni; Maria Barbara Pasanisi; Elizabeth A. Sellars; R. Sean Hill; Jennifer N. Partlow; Rebecca K. Willaert; Jaipreet Bharj; Reza Azizi Malamiri; Hamid Galehdari; Gholamreza Shariati; Reza Maroofian; Marina Mora; Laura E. Swan; Thomas Voit; Francesco J. Conti; Yalda Jamshidi; M. Chiara Manzini
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Daniel P.S. Osborn, Heather L. Pond, Neda Mazaheri, Jeremy Dejardin, Christopher J. Munn, Khaloob Mushref, Edmund S. Cauley, Isabella Moroni, Maria Barbara Pasanisi, Elizabeth A. Sellars, R. Sean Hill, Jennifer N. Partlow, Rebecca K. Willaert, Jaipreet Bharj, Reza Azizi Malamiri, Hamid Galehdari, Gholamreza Shariati, Reza Maroofian, Marina Mora, Laura E. Swan, Thomas Voit, Francesco J. Conti, Yalda Jamshidi, M. Chiara Manzini
      Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.019
  • Detection of Imprinted Genes by Single-Cell Allele-Specific Gene
    • Authors: Federico A. Santoni; Georgios Stamoulis; Marco Garieri; Emilie Falconnet; Pascale Ribaux; Christelle Borel; Stylianos E. Antonarakis
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Human Genetics
      Author(s): Federico A. Santoni, Georgios Stamoulis, Marco Garieri, Emilie Falconnet, Pascale Ribaux, Christelle Borel, Stylianos E. Antonarakis
      Genomic imprinting results in parental-specific gene expression. Imprinted genes are involved in the etiology of rare syndromes and have been associated with common diseases such as diabetes and cancer. Standard RNA bulk cell sequencing applied to whole-tissue samples has been used to detect imprinted genes in human and mouse models. However, lowly expressed genes cannot be detected by using RNA bulk approaches. Here, we report an original and robust method that combines single-cell RNA-seq and whole-genome sequencing into an optimized statistical framework to analyze genomic imprinting in specific cell types and in different individuals. Using samples from the probands of 2 family trios and 3 unrelated individuals, 1,084 individual primary fibroblasts were RNA sequenced and more than 700,000 informative heterozygous single-nucleotide variations (SNVs) were genotyped. The allele-specific coverage per gene of each SNV in each single cell was used to fit a beta-binomial distribution to model the likelihood of a gene being expressed from one and the same allele. Genes presenting a significant aggregate allelic ratio (between 0.9 and 1) were retained to identify of the allelic parent of origin. Our approach allowed us to validate the imprinting status of all of the known imprinted genes expressed in fibroblasts and the discovery of nine putative imprinted genes, thereby demonstrating the advantages of single-cell over bulk RNA-seq to identify imprinted genes. The proposed single-cell methodology is a powerful tool for establishing a cell type-specific map of genomic imprinting.

      PubDate: 2017-02-10T14:18:38Z
      DOI: 10.1016/j.ajhg.2017.01.028
  • InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP
    • Authors: Quan Li; Kai Wang
      Abstract: Publication date: Available online 26 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Quan Li, Kai Wang
      In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.

      PubDate: 2017-01-28T04:01:51Z
      DOI: 10.1016/j.ajhg.2017.01.004
  • Decreased STARD10 Expression Is Associated with Defective Insulin
           Secretion in Humans and Mice
    • Authors: Gaelle R. Carrat; Ming Hu; Marie-Sophie Nguyen-Tu; Pauline Chabosseau; Kyle J. Gaulton; Martijn van de Bunt; Afshan Siddiq; Mario Falchi; Matthias Thurner; Mickaël Canouil; Francois Pattou; Isabelle Leclerc; Timothy J. Pullen; Matthew C. Cane; Priyanka Prabhala; William Greenwald; Anke Schulte; Piero Marchetti; Mark Ibberson; Patrick E. MacDonald; Jocelyn E. Manning Fox; Anna L. Gloyn; Philippe Froguel; Michele Solimena; Mark I. McCarthy; Guy A. Rutter
      Abstract: Publication date: Available online 26 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Gaelle R. Carrat, Ming Hu, Marie-Sophie Nguyen-Tu, Pauline Chabosseau, Kyle J. Gaulton, Martijn van de Bunt, Afshan Siddiq, Mario Falchi, Matthias Thurner, Mickaël Canouil, Francois Pattou, Isabelle Leclerc, Timothy J. Pullen, Matthew C. Cane, Priyanka Prabhala, William Greenwald, Anke Schulte, Piero Marchetti, Mark Ibberson, Patrick E. MacDonald, Jocelyn E. Manning Fox, Anna L. Gloyn, Philippe Froguel, Michele Solimena, Mark I. McCarthy, Guy A. Rutter
      Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.

      PubDate: 2017-01-28T04:01:51Z
      DOI: 10.1016/j.ajhg.2017.01.011
  • Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and
           Intellectual Disability
    • Authors: Yair Anikster; Tobias B. Haack; Thierry Vilboux; Ben Pode-Shakked; Beat Thöny; Nan Shen; Virginia Guarani; Thomas Meissner; Ertan Mayatepek; Friedrich K. Trefz; Dina Marek-Yagel; Aurora Martinez; Edward L. Huttlin; Joao A. Paulo; Riccardo Berutti; Jean-François Benoist; Apolline Imbard; Imen Dorboz; Gali Heimer; Yuval Landau; Limor Ziv-Strasser; May Christine V. Malicdan; Corinne Gemperle-Britschgi; Kirsten Cremer; Hartmut Engels; David Meili; Irene Keller; Rémy Bruggmann; Tim M. Strom; Thomas Meitinger; James C. Mullikin; Gerard Schwartz; Bruria Ben-Zeev; William A. Gahl; J. Wade Harper; Nenad Blau; Georg F. Hoffmann; Holger Prokisch; Thomas Opladen; Manuel Schiff
      Abstract: Publication date: Available online 26 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Yair Anikster, Tobias B. Haack, Thierry Vilboux, Ben Pode-Shakked, Beat Thöny, Nan Shen, Virginia Guarani, Thomas Meissner, Ertan Mayatepek, Friedrich K. Trefz, Dina Marek-Yagel, Aurora Martinez, Edward L. Huttlin, Joao A. Paulo, Riccardo Berutti, Jean-François Benoist, Apolline Imbard, Imen Dorboz, Gali Heimer, Yuval Landau, Limor Ziv-Strasser, May Christine V. Malicdan, Corinne Gemperle-Britschgi, Kirsten Cremer, Hartmut Engels, David Meili, Irene Keller, Rémy Bruggmann, Tim M. Strom, Thomas Meitinger, James C. Mullikin, Gerard Schwartz, Bruria Ben-Zeev, William A. Gahl, J. Wade Harper, Nenad Blau, Georg F. Hoffmann, Holger Prokisch, Thomas Opladen, Manuel Schiff
      Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.

      PubDate: 2017-01-28T04:01:51Z
      DOI: 10.1016/j.ajhg.2017.01.002
  • Practical Approaches for Whole-Genome Sequence Analysis of Heart- and
           Blood-Related Traits
    • Authors: Alanna C. Morrison; Zhuoyi Huang; Bing Yu; Ginger Metcalf; Xiaoming Liu; Christie Ballantyne; Josef Coresh; Fuli Yu; Donna Muzny; Elena Feofanova; Navin Rustagi; Richard Gibbs; Eric Boerwinkle
      Abstract: Publication date: Available online 12 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Alanna C. Morrison, Zhuoyi Huang, Bing Yu, Ginger Metcalf, Xiaoming Liu, Christie Ballantyne, Josef Coresh, Fuli Yu, Donna Muzny, Elena Feofanova, Navin Rustagi, Richard Gibbs, Eric Boerwinkle
      Whole-genome sequencing (WGS) allows for a comprehensive view of the sequence of the human genome. We present and apply integrated methodologic steps for interrogating WGS data to characterize the genetic architecture of 10 heart- and blood-related traits in a sample of 1,860 African Americans. In order to evaluate the contribution of regulatory and non-protein coding regions of the genome, we conducted aggregate tests of rare variation across the entire genomic landscape using a sliding window, complemented by an annotation-based assessment of the genome using predefined regulatory elements and within the first intron of all genes. These tests were performed treating all variants equally as well as with individual variants weighted by a measure of predicted functional consequence. Significant findings were assessed in 1,705 individuals of European ancestry. After these steps, we identified and replicated components of the genomic landscape significantly associated with heart- and blood-related traits. For two traits, lipoprotein(a) levels and neutrophil count, aggregate tests of low-frequency and rare variation were significantly associated across multiple motifs. For a third trait, cardiac troponin T, investigation of regulatory domains identified a locus on chromosome 9. These practical approaches for WGS analysis led to the identification of informative genomic regions and also showed that defined non-coding regions, such as first introns of genes and regulatory domains, are associated with important risk factor phenotypes. This study illustrates the tractable nature of WGS data and outlines an approach for characterizing the genetic architecture of complex traits.

      PubDate: 2017-01-13T03:01:00Z
      DOI: 10.1016/j.ajhg.2016.12.009
  • The Rare-Variant Generalized Disequilibrium Test for Association Analysis
           of Nuclear and Extended Pedigrees with Application to Alzheimer Disease
           WGS Data
    • Authors: Zongxiao He; Di Zhang; Alan E. Renton; Biao Li; Linhai Zhao; Gao T. Wang; Alison M. Goate; Richard Mayeux; Suzanne M. Leal
      Abstract: Publication date: Available online 5 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Zongxiao He, Di Zhang, Alan E. Renton, Biao Li, Linhai Zhao, Gao T. Wang, Alison M. Goate, Richard Mayeux, Suzanne M. Leal
      Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibrium test (GDT) to analyze sequence data obtained from nuclear and extended families. The GDT utilizes genotype differences of all discordant relative pairs to assess associations within a family, and the RV extension combines the single-variant GDT statistic over a genomic region of interest. The RV-GDT has increased power by efficiently incorporating information beyond first-degree relatives and allows for the inclusion of covariates. Using simulated genetic data, we demonstrated that the RV-GDT method has well-controlled type I error rates, even when applied to admixed populations and populations with substructure. It is more powerful than existing family-based RV association methods, particularly for the analysis of extended pedigrees and pedigrees with missing data. We analyzed whole-genome sequence data from families affected by Alzheimer disease to illustrate the application of the RV-GDT. Given the capability of the RV-GDT to adequately control for population admixture or substructure and analyze pedigrees with missing genotype data and its superior power over other family-based methods, it is an effective tool for elucidating the involvement of RVs in the etiology of complex traits.

      PubDate: 2017-01-13T03:01:00Z
      DOI: 10.1016/j.ajhg.2016.12.001
  • The Genetic Architecture of Gene Expression in Peripheral Blood
    • Authors: Luke R. Lloyd-Jones; Alexander Holloway; Allan McRae; Jian Yang; Kerrin Small; Biao Zeng; Andrew Bakshi; Andres Metspalu; Manolis Dermitzakis; Greg Gibson; Tim Spector; Grant Montgomery; Tonu Esko; Peter M. Visscher; Joseph E. Powell
      Abstract: Publication date: Available online 5 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Luke R. Lloyd-Jones, Alexander Holloway, Allan McRae, Jian Yang, Kerrin Small, Biao Zeng, Andrew Bakshi, Andres Metspalu, Manolis Dermitzakis, Greg Gibson, Tim Spector, Grant Montgomery, Tonu Esko, Peter M. Visscher, Joseph E. Powell
      We analyzed the mRNA levels for 36,778 transcript expression traits (probes) from 2,765 individuals to comprehensively investigate the genetic architecture and degree of missing heritability for gene expression in peripheral blood. We identified 11,204 cis and 3,791 trans independent expression quantitative trait loci (eQTL) by using linear mixed models to perform genome-wide association analyses. Furthermore, using information on both closely and distantly related individuals, heritability was estimated for all expression traits. Of the set of expressed probes (15,966), 10,580 (66%) had an estimated narrow-sense heritability (h 2) greater than zero with a mean (median) value of 0.192 (0.142). Across these probes, on average the proportion of genetic variance explained by all eQTL ( h C O J O 2 ) was 31% (0.060/0.192), meaning that 69% is missing, with the sentinel SNP of the largest eQTL explaining 87% (0.052/0.060) of the variance attributed to all identified cis- and trans-eQTL. For the same set of probes, the genetic variance attributed to genome-wide common (MAF > 0.01) HapMap 3 SNPs ( h g 2 ) accounted for on average 48% (0.093/0.192) of h 2. Taken together, the evidence suggests that approximately half the genetic variance for gene expression is not tagged by common SNPs, and of the variance that is tagged by common SNPs, a large proportion can be attributed to identifiable eQTL of large effect, typically in cis. Finally, we present evidence that, compared with a meta-analysis, using individual-level data results in an increase of approximately 50% in power to detect eQTL.

      PubDate: 2017-01-13T03:01:00Z
      DOI: 10.1016/j.ajhg.2016.12.008
  • Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa
    • Authors: Tim Van Damme; Thatjana Gardeitchik; Miski Mohamed; Sergio Guerrero-Castillo; Peter Freisinger; Brecht Guillemyn; Ariana Kariminejad; Daisy Dalloyaux; Sanne van Kraaij; Dirk J. Lefeber; Delfien Syx; Wouter Steyaert; Riet De Rycke; Alexander Hoischen; Erik-Jan Kamsteeg; Sunnie Y. Wong; Monique van Scherpenzeel; Payman Jamali; Ulrich Brandt; Leo Nijtmans; G. Christoph Korenke; Brian H.Y. Chung; Christopher C.Y. Mak; Ingrid Hausser; Uwe Kornak; Björn Fischer-Zirnsak; Tim M. Strom; Thomas Meitinger; Yasemin Alanay; Gulen E. Utine; Peter K.C. Leung; Siavash Ghaderi-Sohi; Paul Coucke; Sofie Symoens; Anne De Paepe; Christian Thiel; Tobias B. Haack; Fransiska Malfait; Eva Morava; Bert Callewaert; Ron A. Wevers
      Abstract: Publication date: Available online 5 January 2017
      Source:The American Journal of Human Genetics
      Author(s): Tim Van Damme, Thatjana Gardeitchik, Miski Mohamed, Sergio Guerrero-Castillo, Peter Freisinger, Brecht Guillemyn, Ariana Kariminejad, Daisy Dalloyaux, Sanne van Kraaij, Dirk J. Lefeber, Delfien Syx, Wouter Steyaert, Riet De Rycke, Alexander Hoischen, Erik-Jan Kamsteeg, Sunnie Y. Wong, Monique van Scherpenzeel, Payman Jamali, Ulrich Brandt, Leo Nijtmans, G. Christoph Korenke, Brian H.Y. Chung, Christopher C.Y. Mak, Ingrid Hausser, Uwe Kornak, Björn Fischer-Zirnsak, Tim M. Strom, Thomas Meitinger, Yasemin Alanay, Gulen E. Utine, Peter K.C. Leung, Siavash Ghaderi-Sohi, Paul Coucke, Sofie Symoens, Anne De Paepe, Christian Thiel, Tobias B. Haack, Fransiska Malfait, Eva Morava, Bert Callewaert, Ron A. Wevers
      Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.

      PubDate: 2017-01-13T03:01:00Z
      DOI: 10.1016/j.ajhg.2016.12.010
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