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Publisher: Elsevier   (Total: 3177 journals)

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Showing 1 - 200 of 3178 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 105, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 42, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 7)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 449, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 29, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 326, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 7, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 13, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 193, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 30, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 1, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 52, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 67, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 7, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 9, SJR: 0.682, CiteScore: 2)
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: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 15, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 25)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 11)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 68)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 433, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 54, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 389, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 487, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 45, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 11, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 54, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 47, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 37, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 272, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 67, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 25, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 217, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 230, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 7, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
American Journal of Human Genetics
Journal Prestige (SJR): 7.45
Citation Impact (citeScore): 8
Number of Followers: 37  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
Published by Elsevier Homepage  [3177 journals]
  • Sex-Based Analysis of De Novo Variants in Neurodevelopmental
           Disorders
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of Human GeneticsAuthor(s): Tychele N. Turner, Amy B. Wilfert, Trygve E. Bakken, Raphael A. Bernier, Micah R. Pepper, Zhancheng Zhang, Rebecca I. Torene, Kyle Retterer, Evan E. EichlerWhile genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.
       
  • Validation Studies for Single Circulating Trophoblast Genetic Testing as a
           Form of Noninvasive Prenatal Diagnosis
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of Human GeneticsAuthor(s): Liesbeth Vossaert, Qun Wang, Roseen Salman, Anne K. McCombs, Vipulkumar Patel, Chunjing Qu, Michael A. Mancini, Dean P. Edwards, Anna Malovannaya, Pengfei Liu, Chad A. Shaw, Brynn Levy, Ronald J. Wapner, Weimin Bi, Amy M. Breman, Ignatia B. Van den Veyver, Arthur L. BeaudetIt has long been appreciated that genetic analysis of fetal or trophoblast cells in maternal blood could revolutionize prenatal diagnosis. We implemented a protocol for single circulating trophoblast (SCT) testing using positive selection by magnetic-activated cell sorting and single-cell low-coverage whole-genome sequencing to detect fetal aneuploidies and copy-number variants (CNVs) at ∼1 Mb resolution. In 95 validation cases, we identified on average 0.20 putative trophoblasts/mL, of which 55% were of high quality and scorable for both aneuploidy and CNVs. We emphasize the importance of analyzing individual cells because some cells are apoptotic, in S-phase, or otherwise of poor quality. When two or more high-quality trophoblast cells were available for singleton pregnancies, there was complete concordance between all trophoblasts unless there was evidence of confined placental mosaicism. SCT results were highly concordant with available clinical data from chorionic villus sampling (CVS) or amniocentesis procedures. Although determining the exact sensitivity and specificity will require more data, this study further supports the potential for SCT testing to become a diagnostic prenatal test.
       
  • Loss of Oxidation Resistance 1, OXR1, Is Associated with an
           Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and
           Lysosomal Dysfunction
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of Human GeneticsAuthor(s): Julia Wang, Justine Rousseau, Emily Kim, Sophie Ehresmann, Yi-Ting Cheng, Lita Duraine, Zhongyuan Zuo, Ye-Jin Park, David Li-Kroeger, Weimin Bi, Lee-Jun Wong, Jill Rosenfeld, Joseph Gleeson, Eissa Faqeih, Fowzan S. Alkuraya, Klaas J. Wierenga, Jiani Chen, Alexandra Afenjar, Caroline Nava, Diane DoummarWe report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
       
  • Integrating Clinical Data and Imputed Transcriptome from GWAS to Uncover
           Complex Disease Subtypes: Applications in Psychiatry and Cardiology
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of Human GeneticsAuthor(s): Liangying Yin, Carlos K.L. Chau, Pak-Chung Sham, Hon-Cheong SoClassifying subjects into clinically and biologically homogeneous subgroups will facilitate the understanding of disease pathophysiology and development of targeted prevention and intervention strategies. Traditionally, disease subtyping is based on clinical characteristics alone, but subtypes identified by such an approach may not conform exactly to the underlying biological mechanisms. Very few studies have integrated genomic profiles (e.g., those from GWASs) with clinical symptoms for disease subtyping. Here we proposed an analytic framework capable of finding complex diseases subgroups by leveraging both GWAS-predicted gene expression levels and clinical data by a multi-view bicluster analysis. This approach connects SNPs to genes via their effects on expression, so the analysis is more biologically relevant and interpretable than a pure SNP-based analysis. Transcriptome of different tissues can also be readily modeled. We also proposed various evaluation metrics for assessing clustering performance. Our framework was able to subtype schizophrenia subjects into diverse subgroups with different prognosis and treatment response. We also applied the framework to the Northern Finland Birth Cohort (NFBC) 1966 dataset and identified high and low cardiometabolic risk subgroups in a gender-stratified analysis. The prediction strength by cross-validation was generally greater than 80%, suggesting good stability of the clustering model. Our results suggest a more data-driven and biologically informed approach to defining metabolic syndrome and subtyping psychiatric disorders. Moreover, we found that the genes “blindly” selected by the algorithm are significantly enriched for known susceptibility genes discovered in GWASs of schizophrenia or cardiovascular diseases. The proposed framework opens up an approach to subject stratification.
       
  • Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and
           Pulmonary Hypoplasia
    • Abstract: Publication date: Available online 21 November 2019Source: The American Journal of Human GeneticsAuthor(s): Ariana Kariminejad, Emmanuelle Szenker-Ravi, Caroline Lekszas, Homa Tajsharghi, Ali-Reza Moslemi, Thomas Naert, Hong Thi Tran, Fatemeh Ahangari, Minoo Rajaei, Mojila Nasseri, Thomas Haaf, Afrooz Azad, Andrea Superti-Furga, Reza Maroofian, Siavash Ghaderi-Sohi, Hossein Najmabadi, Mohammad Reza Abbaszadegan, Kris Vleminckx, Pooneh Nikuei, Bruno ReversadeThe development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.
       
  • Genome-Wide Associations Reveal Human-Mouse Genetic Convergence and
           Modifiers of Myogenesis, CPNE1 and STC2
    • Abstract: Publication date: Available online 21 November 2019Source: The American Journal of Human GeneticsAuthor(s): Ana I. Hernandez Cordero, Natalia M. Gonzales, Clarissa C. Parker, Greta Sokolof, David J. Vandenbergh, Riyan Cheng, Mark Abney, Andrew Sko, Alex Douglas, Abraham A. Palmer, Jennifer S. Gregory, Arimantas LionikasMuscle bulk in adult healthy humans is highly variable even after height, age, and sex are accounted for. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-aged (aged 38–49 years) individuals from the UK Biobank (UKB), we found 182 loci associated with ALM (p < 5 × 10−8). We replicated associations for 78% of these loci (p 
       
  • Making the Most of Clumping and Thresholding for Polygenic Scores
    • Abstract: Publication date: Available online 21 November 2019Source: The American Journal of Human GeneticsAuthor(s): Florian Privé, Bjarni J. Vilhjálmsson, Hugues Aschard, Michael G.B. BlumPolygenic prediction has the potential to contribute to precision medicine. Clumping and thresholding (C+T) is a widely used method to derive polygenic scores. When using C+T, several p value thresholds are tested to maximize predictive ability of the derived polygenic scores. Along with this p value threshold, we propose to tune three other hyper-parameters for C+T. We implement an efficient way to derive thousands of different C+T scores corresponding to a grid over four hyper-parameters. For example, it takes a few hours to derive 123K different C+T scores for 300K individuals and 1M variants using 16 physical cores. We find that optimizing over these four hyper-parameters improves the predictive performance of C+T in both simulations and real data applications as compared to tuning only the p value threshold. A particularly large increase can be noted when predicting depression status, from an AUC of 0.557 (95% CI: [0.544–0.569]) when tuning only the p value threshold to an AUC of 0.592 (95% CI: [0.580–0.604]) when tuning all four hyper-parameters we propose for C+T. We further propose stacked clumping and thresholding (SCT), a polygenic score that results from stacking all derived C+T scores. Instead of choosing one set of hyper-parameters that maximizes prediction in some training set, SCT learns an optimal linear combination of all C+T scores by using an efficient penalized regression. We apply SCT to eight different case-control diseases in the UK biobank data and find that SCT substantially improves prediction accuracy with an average AUC increase of 0.035 over standard C+T.
       
  • Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein,
           Result in Asthenozoospermia and Male Infertility
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of Human GeneticsAuthor(s): Patrick Lorès, Denis Dacheux, Zine-Eddine Kherraf, Jean-Fabrice Nsota Mbango, Charles Coutton, Laurence Stouvenel, Come Ialy-Radio, Amir Amiri-Yekta, Marjorie Whitfield, Alain Schmitt, Caroline Cazin, Maëlle Givelet, Lucile Ferreux, Selima Fourati Ben Mustapha, Lazhar Halouani, Ouafi Marrakchi, Abbas Daneshipour, Elma El Khouri, Marcio Do Cruzeiro, Maryline FavierIn humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed “short tails,” which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.
       
  • TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction
           Causes Severe Brain Developmental Abnormalities
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of Human GeneticsAuthor(s): Laura V. Vandervore, Rachel Schot, Chiara Milanese, Daphne J. Smits, Esmee Kasteleijn, Andrew E. Fry, Daniela T. Pilz, Stefanie Brock, Esra Börklü-Yücel, Marco Post, Nadia Bahi-Buisson, María José Sánchez-Soler, Marjon van Slegtenhorst, Boris Keren, Alexandra Afenjar, Stephanie A. Coury, Wen-Hann Tan, Renske Oegema, Linda S. de Vries, Katherine A. FawcettThe redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.
       
  • A Fast and Accurate Method for Genome-Wide Scale Phenome-Wide G × E
           Analysis and Its Application to UK Biobank
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of Human GeneticsAuthor(s): Wenjian Bi, Zhangchen Zhao, Rounak Dey, Lars G. Fritsche, Bhramar Mukherjee, Seunggeun LeeThe etiology of most complex diseases involves genetic variants, environmental factors, and gene-environment interaction (G × E) effects. Compared with marginal genetic association studies, G × E analysis requires more samples and detailed measure of environmental exposures, and this limits the possible discoveries. Large-scale population-based biobanks with detailed phenotypic and environmental information, such as UK-Biobank, can be ideal resources for identifying G × E effects. However, due to the large computation cost and the presence of case-control imbalance, existing methods often fail. Here we propose a scalable and accurate method, SPAGE (SaddlePoint Approximation implementation of G × E analysis), that is applicable for genome-wide scale phenome-wide G × E studies. SPAGE fits a genotype-independent logistic model only once across the genome-wide analysis in order to reduce computation cost, and SPAGE uses a saddlepoint approximation (SPA) to calibrate the test statistics for analysis of phenotypes with unbalanced case-control ratios. Simulation studies show that SPAGE is 33–79 times faster than the Wald test and 72–439 times faster than the Firth’s test, and SPAGE can control type I error rates at the genome-wide significance level even when case-control ratios are extremely unbalanced. Through the analysis of UK-Biobank data of 344,341 white British European-ancestry samples, we show that SPAGE can efficiently analyze large samples while controlling for unbalanced case-control ratios.
       
  • Bi-allelic Mutations in TTC29 Cause Male Subfertility with
           Asthenoteratospermia in Humans and Mice
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of Human GeneticsAuthor(s): Chunyu Liu, Xiaojin He, Wangjie Liu, Shenmin Yang, Lingbo Wang, Weiyu Li, Huan Wu, Shuyan Tang, Xiaoqing Ni, Jiaxiong Wang, Yang Gao, Shixiong Tian, Lin Zhang, Jiangshan Cong, Zhihua Zhang, Qing Tan, Jingjing Zhang, Hong Li, Yading Zhong, Mingrong LvAs a type of severe asthenoteratospermia, multiple morphological abnormalities of the flagella (MMAF) are characterized by the presence of immotile spermatozoa with severe flagellar malformations. MMAF is a genetically heterogeneous disorder, and the known MMAF-associated genes can only account for approximately 60% of human MMAF cases. Here we conducted whole-exome sequencing and identified bi-allelic truncating mutations of the TTC29 (tetratricopeptide repeat domain 29) gene in three (3.8%) unrelated cases from a cohort of 80 MMAF-affected Han Chinese men. TTC29 is preferentially expressed in the testis, and TTC29 protein contains the tetratricopeptide repeat domains that play an important role in cilia- and flagella-associated functions. All of the men harboring TTC29 mutations presented a typical MMAF phenotype and dramatic disorganization in axonemal and/or other peri-axonemal structures. Immunofluorescence assays of spermatozoa from men harboring TTC29 mutations showed deficiency of TTC29 and remarkably reduced staining of intraflagellar-transport-complex-B-associated proteins (TTC30A and IFT52). We also generated a Ttc29-mutated mouse model through the use of CRISPR-Cas9 technology. Remarkably, Ttc29-mutated male mice also presented reduced sperm motility, abnormal flagellar ultrastructure, and male subfertility. Furthermore, intracytoplasmic sperm injections performed for Ttc29-mutated mice and men harboring TTC29 mutations consistently acquired satisfactory outcomes. Collectively, our experimental observations in humans and mice suggest that bi-allelic mutations in TTC29, as an important genetic pathogeny, can induce MMAF-related asthenoteratospermia. Our study also provided effective guidance for clinical diagnosis and assisted reproduction treatments.
       
  • This Month in The Journal
    • Abstract: Publication date: 7 November 2019Source: The American Journal of Human Genetics, Volume 105, Issue 5Author(s): Sarah Ratzel, Sara B. Cullinan
       
  • CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations
    • Abstract: Publication date: Available online 7 November 2019Source: The American Journal of Human GeneticsAuthor(s): Nina Mann, Franziska Kause, Erik K. Henze, Anant Gharpure, Shirlee Shril, Dervla M. Connaughton, Makiko Nakayama, Verena Klämbt, Amar J. Majmundar, Chen-Han W. Wu, Caroline M. Kolvenbach, Rufeng Dai, Jing Chen, Amelie T. van der Ven, Hadas Ityel, Madeleine J. Tooley, Jameela A. Kari, Lucy Bownass, Sherif El Desoky, Elisa De FrancoCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.
       
  • A Comprehensive Haplotype Targeting Strategy for Allele-Specific HTT
           Suppression in Huntington Disease
    • Abstract: Publication date: Available online 7 November 2019Source: The American Journal of Human GeneticsAuthor(s): Chris Kay, Jennifer A. Collins, Nicholas S. Caron, Luciana de Andrade Agostinho, Hailey Findlay-Black, Lorenzo Casal, Dulika Sumathipala, Vajira H.W. Dissanayake, Mario Cornejo-Olivas, Fiona Baine, Amanda Krause, Jacquie L. Greenberg, Carmen Lúcia Antão Paiva, Ferdinando Squitieri, Michael R. HaydenHuntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.
       
  • Multivariate Genome-Wide Association Analysis of a Cytokine Network
           Reveals Variants with Widespread Immune, Haematological, and
           Cardiometabolic Pleiotropy
    • Abstract: Publication date: Available online 31 October 2019Source: The American Journal of Human GeneticsAuthor(s): Artika P. Nath, Scott C. Ritchie, Nastasiya F. Grinberg, Howard Ho-Fung Tang, Qin Qin Huang, Shu Mei Teo, Ari V. Ahola-Olli, Peter Würtz, Aki S. Havulinna, Kristiina Santalahti, Niina Pitkänen, Terho Lehtimäki, Mika Kähönen, Leo-Pekka Lyytikäinen, Emma Raitoharju, Ilkka Seppälä, Antti-Pekka Sarin, Samuli Ripatti, Aarno Palotie, Markus PerolaCytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.
       
  • Genome Sequencing Explores Complexity of Chromosomal Abnormalities in
           Recurrent Miscarriage
    • Abstract: Publication date: Available online 31 October 2019Source: The American Journal of Human GeneticsAuthor(s): Zirui Dong, Junhao Yan, Fengping Xu, Jianying Yuan, Hui Jiang, Huilin Wang, Haixiao Chen, Lei Zhang, Lingfei Ye, Jinjin Xu, Yuhua Shi, Zhenjun Yang, Ye Cao, Lingyun Chen, Qiaoling Li, Xia Zhao, Jiguang Li, Ao Chen, Wenwei Zhang, Hoi Gin WongRecurrent miscarriage (RM) affects millions of couples globally, and half of them have no demonstrated etiology. Genome sequencing (GS) is an enhanced and novel cytogenetic tool to define the contribution of chromosomal abnormalities in human diseases. In this study we evaluated its utility in RM-affected couples. We performed low-pass GS retrospectively for 1,090 RM-affected couples, all of whom had routine chromosome analysis. A customized sequencing and interpretation pipeline was developed to identify chromosomal rearrangements and deletions/duplications with confirmation by fluorescence in situ hybridization, chromosomal microarray analysis, and PCR studies. Low-pass GS yielded results in 1,077 of 1,090 couples (98.8%) and detected 127 chromosomal abnormalities in 11.7% (126/1,077) of couples; both members of one couple were identified with inversions. Of the 126 couples, 39.7% (50/126) had received former diagnostic results by karyotyping characteristic of normal human male or female karyotypes. Low-pass GS revealed additional chromosomal abnormalities in 50 (4.0%) couples, including eight with balanced translocations and 42 inversions. Follow-up studies of these couples showed a higher miscarriage/fetal-anomaly rate of 5/10 (50%) compared to 21/93 (22.6%) in couples with normal GS, resulting in a relative risk of 2.2 (95% confidence interval, 1.1 to 4.6). In these couples, this protocol significantly increased the diagnostic yield of chromosomal abnormalities per couple (11.7%) in comparison to chromosome analysis (8.0%, chi-square test p = 0.000751). In summary, low-pass GS identified underlying chromosomal aberrations in 1 in 9 RM-affected couples, enabling identification of a subgroup of couples with increased risk of subsequent miscarriage who would benefit from a personalized intervention.
       
  • Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of Human GeneticsAuthor(s): Tariq Masoodi, Abdul K. Siraj, Sarah Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Saif S. Al-Sobhi, Mohammed AlDawish, Fowzan S. Alkuraya, Khawla S. Al-KurayaUnlike many cancers, the pattern of tumor evolution in papillary thyroid cancer (PTC) and its potential role in relapse have not been elucidated. In this study, multi-region whole-exome sequencing (WES) was performed on early-stage PTC tumors (n = 257 tumor regions) from 79 individuals, including 17 who had developed relapse, to understand the temporal and spatial framework within which subclonal mutations catalyze tumor evolution and its potential clinical relevance. Paired primary-relapse tumor tissues were also available for a subset of individuals. The resulting catalog of variants was analyzed to explore evolutionary histories, define clonal and subclonal events, and assess the relationship between intra-tumor heterogeneity and relapse-free survival. The multi-region WES approach was key in correctly classifying subclonal mutations, 40% of which would have otherwise been erroneously considered clonal. We observed both linear and branching evolution patterns in our PTC cohort. A higher burden of subclonal mutations was significantly associated with increased risk of relapse. We conclude that relapse in PTC, while generally rare, does not follow a predictable evolutionary path and that subclonal mutation burden may serve as a prognostic factor. Larger studies utilizing multi-region sequencing in relapsed PTC case subjects with matching primary tissues are needed to confirm these observations.
       
  • A Genocentric Approach to Discovery of Mendelian Disorders
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of Human GeneticsAuthor(s): Adam W. Hansen, Mullai Murugan, He Li, Michael M. Khayat, Liwen Wang, Jill Rosenfeld, B. Kim Andrews, Shalini N. Jhangiani, Zeynep H. Coban Akdemir, Fritz J. Sedlazeck, Allison E. Ashley-Koch, Pengfei Liu, Donna M. Muzny, Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi CopeThe advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.
       
  • Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2
           Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of Human GeneticsAuthor(s): Caroline M. Dias, Jaya Punetha, Céline Zheng, Neda Mazaheri, Abolfazl Rad, Stephanie Efthymiou, Andrea Petersen, Mohammadreza Dehghani, Davut Pehlivan, Jennifer N. Partlow, Jennifer E. Posey, Vincenzo Salpietro, Alper Gezdirici, Reza Azizi Malamiri, Nihal M. Al Menabawy, Laila A. Selim, Mohammad Yahya Vahidi Mehrjardi, Selina Banu, Daniel L. Polla, Edward YangNTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.
       
  • The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia
           Predisposition in Chromosome 16p11.2 Autism Individuals
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of Human GeneticsAuthor(s): Giuliana Giannuzzi, Paul J. Schmidt, Eleonora Porcu, Gilles Willemin, Katherine M. Munson, Xander Nuttle, Rachel Earl, Jacqueline Chrast, Kendra Hoekzema, Davide Risso, Katrin Männik, Pasquelena De Nittis, Ethan D. Baratz, 16p11.2 Consortium, Yann Herault, Xiang Gao, Caroline C. Philpott, Raphael A. Bernier, Zoltan Kutalik, Mark D. Fleming, Evan E. EichlerHuman-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4–BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4–BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e−7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/− and Bola2−/− animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.
       
  • Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1
           Associated with Sleep-Related Oxyhemoglobin Saturation Level
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of Human GeneticsAuthor(s): Jingjing Liang, Brian E. Cade, Karen Y. He, Heming Wang, Jiwon Lee, Tamar Sofer, Stephanie Williams, Ruitong Li, Han Chen, Daniel J. Gottlieb, Daniel S. Evans, Xiuqing Guo, Sina A. Gharib, Lauren Hale, David R. Hillman, Pamela L. Lutsey, Sutapa Mukherjee, Heather M. Ochs-Balcom, Lyle J. Palmer, Jessica RhodesAverage arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1, 2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10−7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.
       
  • Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic
           Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Daniel A. Snellings, Carol J. Gallione, Dewi S. Clark, Nicholas T. Vozoris, Marie E. Faughnan, Douglas A. MarchukHereditary hemorrhagic telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations (VMs) including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function (LoF) mutations in one of three genes, ENG, ACVRL1, or SMAD4, and is inherited as an autosomal-dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple VMs in individuals with HHT occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of VMs. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia through the use of next-generation sequencing. We established phase for seven of nine samples, which confirms that the germline and somatic mutations in all seven samples exist in trans configuration; this is consistent with a genetic two-hit mechanism. These combined data suggest that bi-allelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, VMs in HHT are caused by a Knudsonian two-hit mechanism.
       
  • Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and
           Photophobia
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Lynn M. Boyden, Lihi Atzmony, Claire Hamilton, Jing Zhou, Young H. Lim, Ronghua Hu, John Pappas, Rachel Rabin, Joseph Ekstien, Yoel Hirsch, Julie Prendiville, Richard P. Lifton, Shawn Ferguson, Keith A. ChoateWe describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.
       
  • Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and
           Lissencephaly Spectrum Disorders
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Tadahiro Mitani, Jaya Punetha, Ibrahim Akalin, Davut Pehlivan, Mateusz Dawidziuk, Zeynep Coban Akdemir, Sarenur Yilmaz, Ezgi Aslan, Jill V. Hunter, Hadia Hijazi, Christopher M. Grochowski, Shalini N. Jhangiani, Ender Karaca, Jawid M. Fatih, Piotr Iwanowski, Tomasz Gambin, Pawel Wlasienko, Alicja Goszczanska-Ciuchta, Monika Bekiesinska-Figatowska, Masoumeh HosseiniLissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.
       
  • Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of
           Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Hessa S. Alsaif, Mohammad Al-Owain, Martin E. Barrios-Llerena, Ghada Gosadi, Yousef binamer, David Devadason, Jane Ravenscroft, Mohnish Suri, Fowzan S. AlkurayaMEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is an autosomal-recessive disorder caused by bi-allelic mutations in AP1S1, encoding the small σ subunit of the AP-1 complex. Central to the pathogenesis of MEDNIK syndrome is abnormal AP-1-mediated trafficking of copper transporters; this abnormal trafficking results in a hybrid phenotype combining the copper-deficiency-related characteristics of Menkes disease and the copper-toxicity-related characteristics of Wilson disease. We describe three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1, encoding the large β subunit of the AP-1 complex. Similar to individuals with MEDNIK syndrome, the affected individuals we report display abnormal copper metabolism, evidenced by low plasma copper and ceruloplasmin, but lack evidence of copper toxicity in the liver. Functional characterization of fibroblasts derived from affected individuals closely resembles the abnormal ATP7A trafficking described in MEDNIK syndrome both at baseline and in response to copper treatment. Taken together, our results expand the list of inborn errors of copper metabolism.
       
  • RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe
           Short Stature
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Cedric Le Caignec, Benjamin Ory, François Lamoureux, Marie-Francoise O’Donohue, Emilien Orgebin, Pierre Lindenbaum, Stéphane Téletchéa, Manon Saby, Anna Hurst, Katherine Nelson, Shawn R. Gilbert, Yael Wilnai, Leonid Zeitlin, Eitan Segev, Robel Tesfaye, Mathilde Nizon, Benjamin Cogne, Stéphane Bezieau, Loic Geoffroy, Antoine HamelVariants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.
       
  • De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with
           Hydrocephalus and Randomization of Left/Right Body Asymmetry
    • Abstract: Publication date: Available online 17 October 2019Source: The American Journal of Human GeneticsAuthor(s): Julia Wallmeier, Diana Frank, Amelia Shoemark, Tabea Nöthe-Menchen, Sandra Cindric, Heike Olbrich, Niki T. Loges, Isabella Aprea, Gerard W. Dougherty, Petra Pennekamp, Thomas Kaiser, Hannah M. Mitchison, Claire Hogg, Siobhán B. Carr, Maimoona A. Zariwala, Thomas Ferkol, Margaret W. Leigh, Stephanie D. Davis, Jeffrey Atkinson, Susan K. DutcherHydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.
       
  • Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data
    • Abstract: Publication date: Available online 10 October 2019Source: The American Journal of Human GeneticsAuthor(s): Stuart Aitken, Helen V. Firth, Jeremy McRae, Mihail Halachev, Usha Kini, Michael J. Parker, Melissa M. Lees, Katherine Lachlan, Ajoy Sarkar, Shelagh Joss, Miranda Splitt, Shane McKee, Andrea H. Németh, Richard H. Scott, Caroline F. Wright, Joseph A. Marsh, Matthew E. Hurles, David R. FitzPatrick, T.W. Fitzgerald, S.S. GeretyTrio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.
       
  • Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental
           Delay, and Short Stature
    • Abstract: Publication date: Available online 10 October 2019Source: The American Journal of Human GeneticsAuthor(s): Muhammad Ansar, Hyung-lok Chung, Ali Al-Otaibi, Mohammad Nael Elagabani, Thomas A. Ravenscroft, Sohail A. Paracha, Ralf Scholz, Tayseer Abdel Magid, Muhammad T. Sarwar, Sayyed Fahim Shah, Azhar Ali Qaisar, Periklis Makrythanasis, Paul C. Marcogliese, Erik-Jan Kamsteeg, Emilie Falconnet, Emmanuelle Ranza, Federico A. Santoni, Hesham Aldhalaan, Ali Al-Asmari, Eissa Ali FaqeihWe report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.
       
  • Characterization of Prevalence and Health Consequences of Uniparental
           Disomy in Four Million Individuals from the General Population
    • Abstract: Publication date: Available online 10 October 2019Source: The American Journal of Human GeneticsAuthor(s): Priyanka Nakka, Samuel Pattillo Smith, Anne H. O’Donnell-Luria, Kimberly F. McManus, Michelle Agee, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Barry Hicks, David A. Hinds, Ethan M. Jewett, Yunxuan Jiang, Keng-Han Lin, Jennifer C. McCreight, Karen E. Huber, Aaron Kleinman, Nadia K. LittermanMeiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ∼3,300 case subjects for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD across 4,400,363 consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. We estimate that UPD is twice as common as previously thought, and we present a machine-learning framework to detect UPD using ROH. While we find a nominally significant association between UPD of chromosome 22 and autism risk, we do not find significant associations between UPD and deleterious traits in the 23andMe database.
       
  • Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by
           Serological Subphenotype
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Chikashi Terao, Boel Brynedal, Zuomei Chen, Xia Jiang, Helga Westerlind, Monika Hansson, Per-Johan Jakobsson, Karin Lundberg, Karl Skriner, Guy Serre, Johan Rönnelid, Linda Mathsson-Alm, Mikael Brink, Solbritt Rantapää Dahlqvist, Leonid Padyukov, Peter K. Gregersen, Anne Barton, Lars Alfredsson, Lars Klareskog, Soumya Raychaudhuri
       
  • Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation
           Characterized by Marfanoid Habitus and Cognitive Impairment
    • Abstract: Publication date: Available online 3 October 2019Source: The American Journal of Human GeneticsAuthor(s): Sarah K. Fiordaliso, Aiko Iwata-Otsubo, Alyssa L. Ritter, Mathieu Quesnel-Vallières, Katsunori Fujiki, Eriko Nishi, Miroslava Hancarova, Noriko Miyake, Jenny E.V. Morton, Sangmoon Lee, Karl Hackmann, Masashige Bando, Koji Masuda, Ryuichiro Nakato, Michiko Arakawa, Elizabeth Bhoj, Dong Li, Hakon Hakonarson, Ryojun Takeda, Margaret HarrNKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.
       
  • De Novo Pathogenic Variants in N-cadherin Cause a Syndromic
           Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular,
           and Genital Defects
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Andrea Accogli, Sara Calabretta, Judith St-Onge, Nassima Boudrahem-Addour, Alexandre Dionne-Laporte, Pascal Joset, Silvia Azzarello-Burri, Anita Rauch, Joel Krier, Elizabeth Fieg, Juan C. Pallais, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. AzamianCadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).
       
  • Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein
           2, Leads to Lissencephaly, Subcortical Heterotopia, and Global
           Developmental Delay
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Sangmoon Lee, Dillon Y. Chen, Maha S. Zaki, Reza Maroofian, Henry Houlden, Nataliya Di Donato, Dalia Abdin, Heba Morsy, Ghayda M. Mirzaa, William B. Dobyns, Jennifer McEvoy-Venneri, Valentina Stanley, Kiely N. James, Grazia M.S. Mancini, Rachel Schot, Tugba Kalayci, Umut Altunoglu, Ehsan Ghayoor Karimiani, Lauren Brick, Mariya KozenkoLissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, “ribbon-like” heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.
       
  • A Rare Variant Nonparametric Linkage Method for Nuclear and Extended
           Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Linhai Zhao, Zongxiao He, Di Zhang, Gao T. Wang, Alan E. Renton, Badri N. Vardarajan, Michael Nothnagel, Alison M. Goate, Richard Mayeux, Suzanne M. LealTo analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g.,>50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.
       
  • Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic
           Mosaicism: A Five-Year Cumulative Cohort
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Samantha N. McNulty, Michael J. Evenson, Meagan M. Corliss, Latisha D. Love-Gregory, Molly C. Schroeder, Yang Cao, Yi-Shan Lee, Beth A. Drolet, Julie A. Neidich, Catherine E. Cottrell, Jonathan W. HeuselDisorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
       
  • This Month in The Journal
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Sarah Ratzel, Sara B. Cullinan
       
  • Estimating the Genome-wide Mutation Rate with Three-Way Identity by
           Descent
    • Abstract: Publication date: Available online 3 October 2019Source: The American Journal of Human GeneticsAuthor(s): Xiaowen Tian, Brian L. Browning, Sharon R. BrowningThe two primary methods for estimating the genome-wide mutation rate have been counting de novo mutations in parent-offspring trios and comparing sequence data between closely related species. With parent-offspring trio analysis it is difficult to control for genotype error, and resolution is limited because each trio provides information from only two meioses. Inter-species comparison is difficult to calibrate due to uncertainty in the number of meioses separating species, and it can be biased by selection and by changing mutation rates over time. An alternative class of approaches for estimating mutation rates that avoids these limitations is based on identity by descent (IBD) segments that arise from common ancestry within the past few thousand years. Existing IBD-based methods are limited to highly inbred samples, or lack robustness to genotype error and error in the estimated demographic history. We present an IBD-based method that uses sharing of IBD segments among sets of three individuals to estimate the mutation rate. Our method is applicable to accurately phased genotype data, such as parent-offspring trio data phased using Mendelian rules of inheritance. Unlike standard parent-offspring analysis, our method utilizes distant relationships and is robust to genotype error. We apply our method to data from 1,307 European-ancestry individuals in the Framingham Heart Study sequenced by the NHLBI TOPMed project. We obtain an estimate of 1.29 × 10−8 mutations per base pair per meiosis with a 95% confidence interval of [1.02 × 10−8, 1.56 × 10−8].
       
  • Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result
           in Transient Hypomyelination during Infancy
    • Abstract: Publication date: Available online 3 October 2019Source: The American Journal of Human GeneticsAuthor(s): Huifang Yan, Guy Helman, Swetha E. Murthy, Haoran Ji, Joanna Crawford, Thomas Kubisiak, Stephen J. Bent, Jiangxi Xiao, Ryan J. Taft, Adam Coombs, Ye Wu, Ana Pop, Dongxiao Li, Linda S. de Vries, Yuwu Jiang, Gajja S. Salomons, Marjo S. van der Knaap, Ardem Patapoutian, Cas Simons, Margit BurmeisterMechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.
       
  • Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in
           a Highly Consanguineous Population
    • Abstract: Publication date: 3 October 2019Source: The American Journal of Human Genetics, Volume 105, Issue 4Author(s): Dorota Monies, Mohammed Abouelhoda, Mirna Assoum, Nabil Moghrabi, Rafiullah Rafiullah, Naif Almontashiri, Mohammed Alowain, Hamad Alzaidan, Moeen Alsayed, Shazia Subhani, Edward Cupler, Maha Faden, Amal Alhashem, Alya Qari, Aziza Chedrawi, Hisham Aldhalaan, Wesam Kurdi, Sameena Khan, Zuhair Rahbeeni, Maha Alotaibi
       
  • Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by
           Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision
           Medicine Program
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Chloé Sarnowski, Aaron Leong, Laura M. Raffield, Peitao Wu, Paul S. de Vries, Daniel DiCorpo, Xiuqing Guo, Huichun Xu, Yongmei Liu, Xiuwen Zheng, Yao Hu, Jennifer A. Brody, Mark O. Goodarzi, Bertha A. Hidalgo, Heather M. Highland, Deepti Jain, Ching-Ti Liu, Rakhi P. Naik, Jeffrey R. O’Connell, James A. PerryHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
       
  • A Randomized, Controlled Trial of the Analytic and Diagnostic Performance
           of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Stephen F. Kingsmore, Julie A. Cakici, Michelle M. Clark, Mary Gaughran, Michele Feddock, Sergey Batalov, Matthew N. Bainbridge, Jeanne Carroll, Sara A. Caylor, Christina Clarke, Yan Ding, Katarzyna Ellsworth, Lauge Farnaes, Amber Hildreth, Charlotte Hobbs, Kiely James, Cyrielle I. Kint, Jerica Lenberg, Shareef Nahas, Lance PrinceThe second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96 h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2 days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6 days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.
       
  • Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in
           Genome-wide Association Studies
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Huaying Fang, Qin Hui, Julie Lynch, Jacqueline Honerlaw, Themistocles L. Assimes, Jie Huang, Marijana Vujkovic, Scott M. Damrauer, Saiju Pyarajan, J. Michael Gaziano, Scott L. DuVall, Christopher J. O’Donnell, Kelly Cho, Kyong-Mi Chang, Peter W.F. Wilson, Philip S. Tsao, J. Michael Gaziano, Rachel Ramoni, Jim Breeling, Kyong-Mi ChangLarge-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.
       
  • Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate
           with Cancer and Autism Phenotypes in Cowden Syndrome and
           Bannayan-Riley-Ruvalcaba Syndrome
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Lamis Yehia, Ying Ni, Fang Feng, Marilyn Seyfi, Tammy Sadler, Thomas W. Frazier, Charis EngGermline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10−3), but reduced citrate (p = 5.0 × 10−4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10−3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10−4). Importantly, we identified fumarate (p = 1.9 × 10−2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.
       
  • Autosomal-Recessive Mutations in MESD Cause Osteogenesis
           Imperfecta
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Shahida Moosa, Guilherme L. Yamamoto, Lutz Garbes, Katharina Keupp, Ana Beleza-Meireles, Carolina Araujo Moreno, Eugenia Ribeiro Valadares, Sérgio B. de Sousa, Sofia Maia, Jorge Saraiva, Rachel S. Honjo, Chong Ae Kim, Hamilton Cabral de Menezes, Ekkehart Lausch, Pablo Villavicencio Lorini, Arsonval Lamounier, Tulio Canella Bezerra Carniero, Cecilia Giunta, Marianne Rohrbach, Marco JannerOsteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.
       
  • Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual
           Disability and Microcephaly
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Elodie M. Richard, Daniel L. Polla, Muhammad Zaman Assir, Minerva Contreras, Mohsin Shahzad, Asma A. Khan, Attia Razzaq, Javed Akram, Moazzam N. Tarar, Thomas A. Blanpied, Zubair M. Ahmed, Rami Abou Jamra, Dagmar Wieczorek, Hans van Bokhoven, Sheikh Riazuddin, Saima RiazuddinIntellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.
       
  • Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate
           Genes for Cardiometabolic Traits
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Chelsea K. Raulerson, Arthur Ko, John C. Kidd, Kevin W. Currin, Sarah M. Brotman, Maren E. Cannon, Ying Wu, Cassandra N. Spracklen, Anne U. Jackson, Heather M. Stringham, Ryan P. Welch, Christian Fuchsberger, Adam E. Locke, Narisu Narisu, Aldons J. Lusis, Mete Civelek, Terrence S. Furey, Johanna Kuusisto, Francis S. Collins, Michael BoehnkeGenome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL;
       
  • GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported
           Adult Hearing Difficulty in UK Biobank
    • Abstract: Publication date: Available online 26 September 2019Source: The American Journal of Human GeneticsAuthor(s): Helena R.R. Wells, Maxim B. Freidin, Fatin N. Zainul Abidin, Antony Payton, Piers Dawes, Kevin J. Munro, Cynthia C. Morton, David R. Moore, Sally J. Dawson, Frances M.K. WilliamsAge-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E−08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.
       
  • Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of
           Homozygosity
    • Abstract: Publication date: Available online 19 September 2019Source: The American Journal of Human GeneticsAuthor(s): Zachary A. Szpiech, Angel C.Y. Mak, Marquitta J. White, Donglei Hu, Celeste Eng, Esteban G. Burchard, Ryan D. HernandezRuns of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.
       
  • cis Elements that Mediate RNA Polymerase II Pausing Regulate
           Human Gene Expression
    • Abstract: Publication date: Available online 5 September 2019Source: The American Journal of Human GeneticsAuthor(s): Jason A. Watts, Joshua Burdick, Jillian Daigneault, Zhengwei Zhu, Christopher Grunseich, Alan Bruzel, Vivian G. CheungAberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes including MYO1E and SESN2, RNA Pol II pauses at precise nucleotide locations. Characterization of these sites shows that RNA Pol II pauses at GC-rich regions that are marked by a sequence motif. Sixty-five percent of the pause sites are cytosines. By differential allelic gene expression analysis, we showed in our samples and a population dataset from the Genotype-Tissue Expression (GTEx) consortium that genes with more paused polymerase have lower expression levels. Furthermore, mutagenesis of the pause sites led to a significant increase in promoter activities. Thus, our data uncover that RNA Pol II pauses precisely at sites with distinct sequence features that in turn regulate gene expression.
       
  • Loss of SMPD4 Causes a Developmental Disorder Characterized by
           Microcephaly and Congenital Arthrogryposis
    • Abstract: Publication date: Available online 5 September 2019Source: The American Journal of Human GeneticsAuthor(s): Pamela Magini, Daphne J. Smits, Laura Vandervore, Rachel Schot, Marta Columbaro, Esmee Kasteleijn, Mees van der Ent, Flavia Palombo, Maarten H. Lequin, Marjolein Dremmen, Marie Claire Y. de Wit, Mariasavina Severino, Maria Teresa Divizia, Pasquale Striano, Natalia Ordonez-Herrera, Amal Alhashem, Ahmed Al Fares, Malak Al Ghamdi, Arndt Rolfs, Peter BauerSphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
       
 
 
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