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  • Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-26
    Andrew E. Fry; Christopher Marra; Anna V. Derrick; William O. Pickrell; Adam T. Higgins; Johann te Water Naude; Martin A. McClatchey; Sally J. Davies; Kay A. Metcalfe; Hui Jeen Tan; Rajiv Mohanraj; Shivaram Avula; Denise Williams; Lauren I. Brady; Ronit Mesterman; Mark A. Tarnopolsky; Yuehua Zhang; Ying Yang; Seo-Kyung Chung

    Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome

    更新日期:2020-11-27
  • Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-25
    Fatema Alzahrani; Hiroyuki Kuwahara; Yongkang Long; Mohammed Al-Owain; Mohamed Tohary; Moeenaldeen AlSayed; Mohammed Mahnashi; Lana Fathi; Maha Alnemer; Mohamed H. Al-Hamed; Gabrielle Lemire; Kym M. Boycott; Mais Hashem; Wenkai Han; Almundher Al-Maawali; Feisal Al Mahrizi; Khalid Al-Thihli; Xin Gao; Fowzan S. Alkuraya

    We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles

    更新日期:2020-11-25
  • BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-23
    Scott Barish; Tahsin Stefan Barakat; Brittany C. Michel; Nazar Mashtalir; Jennifer B. Phillips; Alfredo M. Valencia; Berrak Ugur; Jeremy Wegner; Tiana M. Scott; Brett Bostwick; David R. Murdock; Hongzheng Dai; Elena Perenthaler; Anita Nikoncuk; Marjon van Slegtenhorst; Alice S. Brooks; Boris Keren; Hugo J. Bellen

    SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function

    更新日期:2020-11-23
  • DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-23
    Ronen Schneider; Konstantin Deutsch; Gregory J. Hoeprich; Jonathan Marquez; Tobias Hermle; Daniela A. Braun; Steve Seltzsam; Thomas M. Kitzler; Youying Mao; Florian Buerger; Amar J. Majmundar; Ana C. Onuchic-Whitford; Caroline M. Kolvenbach; Luca Schierbaum; Sophia Schneider; Abdul A. Halawi; Makiko Nakayama; Nina Mann; Friedhelm Hildebrandt

    The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney

    更新日期:2020-11-23
  • Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-23
    Anna R. Duncan; Antonio Vitobello; Stephan C. Collins; Valerie E. Vancollie; Christopher J. Lelliott; Lance Rodan; Jiahai Shi; Ann R. Seman; Emanuele Agolini; Antonio Novelli; Paolo Prontera; Maria J. Guillen Sacoto; Teresa Santiago-Sim; Aurélien Trimouille; Cyril Goizet; Mathilde Nizon; Ange-Line Bruel; Christophe Philippe; Pankaj B. Agrawal

    KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort

    更新日期:2020-11-23
  • A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl−/H+-Exchanger, Causes Early-Onset Neurodegeneration
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-19
    Maya M. Polovitskaya; Carlo Barbini; Diego Martinelli; Frederike L. Harms; F. Sessions Cole; Paolo Calligari; Gianfranco Bocchinfuso; Lorenzo Stella; Andrea Ciolfi; Marcello Niceta; Teresa Rizza; Marwan Shinawi; Kathleen Sisco; Jessika Johannsen; Jonas Denecke; Rosalba Carrozzo; Daniel J. Wegner; Kerstin Kutsche; Thomas J. Jentsch

    Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl−/H+ exchangers function as electric shunts for proton pumping and in

    更新日期:2020-11-19
  • Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-19
    Sandra Donkervoort; Carl E. Kutzner; Ying Hu; Xavière Lornage; John Rendu; Tanya Stojkovic; Jonathan Baets; Sarah B. Neuhaus; Jantima Tanboon; Reza Maroofian; Véronique Bolduc; Magdalena Mroczek; Stefan Conijn; Nancy L. Kuntz; Ana Töpf; Soledad Monges; Fabiana Lubieniecki; Riley M. McCarty; Carsten G. Bönnemann

    The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice

    更新日期:2020-11-19
  • Multiplexed Functional Assessment of Genetic Variants in CARD11
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-16
    Iana Meitlis; Eric J. Allenspach; Bradly M. Bauman; Isabelle Q. Phan; Gina Dabbah; Erica G. Schmitt; Nathan D. Camp; Troy R. Torgerson; Deborah A. Nickerson; Michael J. Bamshad; David Hagin; Christopher R. Luthers; Jeffrey R. Stinson; Jessica Gray; Ingrid Lundgren; Joseph A. Church; Manish J. Butte; Mike B. Jordan; Richard G. James

    Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a “cloning-free” saturation genome editing approach in a diploid cell line to simultaneously

    更新日期:2020-11-16
  • De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-12
    Catherine Rodger; Elisabetta Flex; Rachel J. Allison; Alba Sanchis-Juan; Marcia A. Hasenahuer; Serena Cecchetti; Courtney E. French; James R. Edgar; Giovanna Carpentieri; Andrea Ciolfi; Francesca Pantaleoni; Alessandro Bruselles; Roberta Onesimo; Giuseppe Zampino; Francesca Marcon; Ester Siniscalchi; Melissa Lees; Evan Reid

    The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth

    更新日期:2020-11-12
  • VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-12
    Katie G. Seu; Lisa R. Trump; Sana Emberesh; Robert B. Lorsbach; Clarissa Johnson; Jessica Meznarich; Hunter R. Underhill; Stella T. Chou; Haripriya Sakthivel; Nicolas N. Nassar; Kalani J. Seu; Lionel Blanc; Wenying Zhang; Carolyn M. Lutzko; Theodosia A. Kalfa

    The Congenital Dyserythropoietic Anemia (CDA) Registry was established with the goal to facilitate investigations of natural history, biology, and molecular pathogenetic mechanisms of CDA. Three unrelated individuals enrolled in the registry had a syndrome characterized by CDA and severe neurodevelopmental delay. They were found to have missense mutations in VPS4A, a gene coding for an ATPase that

    更新日期:2020-11-12
  • A Multi-omic Integrative Scheme Characterizes Tissues of Action at Loci Associated with Type 2 Diabetes
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-12
    Jason M. Torres; Moustafa Abdalla; Anthony Payne; Juan Fernandez-Tajes; Matthias Thurner; Vibe Nylander; Anna L. Gloyn; Anubha Mahajan; Mark I. McCarthy

    Resolving the molecular processes that mediate genetic risk remains a challenge because most disease-associated variants are non-coding and functional characterization of these signals requires knowledge of the specific tissues and cell-types in which they operate. To address this challenge, we developed a framework for integrating tissue-specific gene expression and epigenomic maps to obtain “tissue-of-action”

    更新日期:2020-11-12
  • RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-06
    Elizabeth E. Palmer; Renee Carroll; Marie Shaw; Raman Kumar; Andre E. Minoche; Melanie Leffler; Lucinda Murray; Rebecca Macintosh; Dale Wright; Chris Troedson; Fiona McKenzie; Sharron Townshend; Michelle Ward; Urwah Nawaz; Anja Ravine; Cassandra K. Runke; Erik C. Thorland; Marybeth Hummel; Jozef Gecz

    Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder

    更新日期:2020-11-06
  • Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-06
    Pauline E. Schneeberger; Leonie von Elsner; Emma L. Barker; Peter Meinecke; Iris Marquardt; Malik Alawi; Katharina Steindl; Pascal Joset; Anita Rauch; Petra J.G. Zwijnenburg; Marjan M. Weiss; Catherine L.R. Merry; Kerstin Kutsche

    Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three

    更新日期:2020-11-06
  • The Practice of Anti-racist Science Requires an Internationalist Perspective
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-05
    Richard S. Cooper; Charles N. Rotimi

    Recent protests by a large segment of the US population over the health and socioeconomic damages caused by structural racism highlight the long history of discrimination against Black Americans. There is a great need for a realignment of race, biomedical research and clinical practice in the US and globally.

    更新日期:2020-11-06
  • Analogies in Genomics Policymaking: Debates and Drawbacks
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-05
    John A. Lynch; Aaron J. Goldenberg; Nanibaa’ A. Garrison; Kyle B. Brothers

    The analogy between genomics and imaging has been an important touchstone in the debate on how secondary findings should be handled in both clinical and research genomics contexts. However, a critical eye is needed to understand whether an analogy like this one provides an adequate basis for policymaking in genomics. Genomics and imaging are undoubtedly similar in certain ways, but whether that similarity

    更新日期:2020-11-06
  • Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-05
    Suzanne E. de Bruijn; Alessia Fiorentino; Daniele Ottaviani; Stephanie Fanucchi; Uirá S. Melo; Julio C. Corral-Serrano; Timo Mulders; Michalis Georgiou; Carlo Rivolta; Nikolas Pontikos; Gavin Arno; Lisa Roberts; Jacquie Greenberg; Silvia Albert; Christian Gilissen; Marco Aben; George Rebello; Simon Mead; Alison J. Hardcastle

    The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized

    更新日期:2020-11-06
  • Cancer PRSweb: An Online Repository with Polygenic Risk Scores for Major Cancer Traits and Their Evaluation in Two Independent Biobanks
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-28
    Lars G. Fritsche; Snehal Patil; Lauren J. Beesley; Peter VandeHaar; Maxwell Salvatore; Ying Ma; Robert B. Peng; Daniel Taliun; Xiang Zhou; Bhramar Mukherjee

    To facilitate scientific collaboration on polygenic risk scores (PRSs) research, we created an extensive PRS online repository for 35 common cancer traits integrating freely available genome-wide association studies (GWASs) summary statistics from three sources: published GWASs, the NHGRI-EBI GWAS Catalog, and UK Biobank-based GWASs. Our framework condenses these summary statistics into PRSs using

    更新日期:2020-11-06
  • Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-05
    Iris Kramer; Maartje J. Hooning; Nasim Mavaddat; Michael Hauptmann; Renske Keeman; Ewout W. Steyerberg; Daniele Giardiello; Antonis C. Antoniou; Paul D.P. Pharoah; Sander Canisius; Zumuruda Abu-Ful; Irene L. Andrulis; Hoda Anton-Culver; Kristan J. Aronson; Annelie Augustinsson; Heiko Becher; Matthias W. Beckmann; Sabine Behrens; Marjanka K. Schmidt

    Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast

    更新日期:2020-11-06
  • A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-07
    Elena V. Feofanova; Han Chen; Yulin Dai; Peilin Jia; Megan L. Grove; Alanna C. Morrison; Qibin Qi; Martha Daviglus; Jianwen Cai; Kari E. North; Cathy C. Laurie; Robert C. Kaplan; Eric Boerwinkle; Bing Yu

    Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants

    更新日期:2020-11-06
  • Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-07
    Katherine A. Owen; Andrew Price; Hannah Ainsworth; Bryce N. Aidukaitis; Prathyusha Bachali; Michelle D. Catalina; James M. Dittman; Timothy D. Howard; Kathryn M. Kingsmore; Adam C. Labonte; Miranda C. Marion; Robert D. Robl; Kip D. Zimmerman; Carl D. Langefeld; Amrie C. Grammer; Peter E. Lipsky

    Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations

    更新日期:2020-11-06
  • Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-05
    Rebecca W.Y. Chan; Lee Serpas; Meng Ni; Stefano Volpi; Linda T. Hiraki; Lai-Shan Tam; Ali Rashidfarrokhi; Priscilla C.H. Wong; Lydia H.P. Tam; Yueyang Wang; Peiyong Jiang; Alice S.H. Cheng; Wenlei Peng; Diana S.C. Han; Patty P.P. Tse; Pik Ki Lau; Wing-Shan Lee; Alberto Magnasco; Y.M. Dennis Lo

    Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3

    更新日期:2020-11-06
  • Probabilistic Estimation of Identity by Descent Segment Endpoints and Detection of Recent Selection
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-13
    Sharon R. Browning; Brian L. Browning

    Most methods for fast detection of identity by descent (IBD) segments report identity by state segments without any quantification of the uncertainty in the endpoints and lengths of the IBD segments. We present a method for determining the posterior probability distribution of IBD segment endpoints. Our approach accounts for genotype errors, recent mutations, and gene conversions which disrupt DNA

    更新日期:2020-11-06
  • Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-23
    Faycal Guedj; Ashley E. Siegel; Jeroen L.A. Pennings; Fatimah Alsebaa; Lauren J. Massingham; Umadevi Tantravahi; Diana W. Bianchi

    Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this

    更新日期:2020-11-06
  • Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-26
    Laura M. Amendola; Kathleen Muenzen; Leslie G. Biesecker; Kevin M. Bowling; Greg M. Cooper; Michael O. Dorschner; Catherine Driscoll; Ann Katherine M. Foreman; Katie Golden-Grant; John M. Greally; Lucia Hindorff; Dona Kanavy; Vaidehi Jobanputra; Jennifer J. Johnston; Eimear E. Kenny; Shannon McNulty; Priyanka Murali; Jeffrey Ou; Gail P. Jarvik

    Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore

    更新日期:2020-11-06
  • An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-05
    David P. Dimmock; Michelle M. Clark; Mary Gaughran; Julie A. Cakici; Sara A. Caylor; Christina Clarke; Michele Feddock; Shimul Chowdhury; Lisa Salz; Cynthia Cheung; Lynne M. Bird; Charlotte Hobbs; Kristen Wigby; Lauge Farnaes; Cinnamon S. Bloss; Stephen F. Kingsmore

    The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of

    更新日期:2020-11-06
  • A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-05
    Julie A. Cakici; David P. Dimmock; Sara A. Caylor; Mary Gaughran; Christina Clarke; Cynthia Triplett; Michelle M. Clark; Stephen F. Kingsmore; Cinnamon S. Bloss

    Rapid diagnostic genomic sequencing recently became feasible for infants in intensive care units (ICUs). However, research regarding parents’ perceived utility, adequacy of consent, and potential harms and benefits is lacking. Herein we report results of parental surveys of these domains from the second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study, a randomized, controlled

    更新日期:2020-11-06
  • NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-11-05
    Hui Guo; Qiumeng Zhang; Rujia Dai; Bin Yu; Kendra Hoekzema; Jieqiong Tan; Senwei Tan; Xiangbin Jia; Wendy K. Chung; Rebecca Hernan; Fowzan S. Alkuraya; Ahood Alsulaiman; Mohammad A. Al-Muhaizea; Gaetan Lesca; Linda Pons; Audrey Labalme; Linda Laux; Emily Bryant; Kun Xia

    NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals

    更新日期:2020-11-06
  • Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-14
    Adrian Palencia-Campos; Phillip C. Aoto; Erik M.F. Machal; Ana Rivera-Barahona; Patricia Soto-Bielicka; Daniela Bertinetti; Blaine Baker; Lily Vu; Francesca Piceci-Sparascio; Isabella Torrente; Eveline Boudin; Silke Peeters; Wim Van Hul; Celine Huber; Dominique Bonneau; Michael S. Hildebrand; Matthew Coleman; Melanie Bahlo; Victor L. Ruiz-Perez

    PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense

    更新日期:2020-11-06
  • Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-13
    Fleur S. van Dijk; Oliver Semler; Julia Etich; Anna Köhler; Juan A. Jimenez-Estrada; Nathalie Bravenboer; Lauria Claeys; Elise Riesebos; Sejla Gegic; Sander R. Piersma; Connie R. Jimenez; Quinten Waisfisz; Carmen-Lisset Flores; Julian Nevado; Arjan J. Harsevoort; Guus J.M. Janus; Anton A.M. Franken; Astrid M. van der Sar; Dimitra Micha

    Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like

    更新日期:2020-11-06
  • Lessons Learned from Bugs in Models of Human History
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-01
    Aaron P. Ragsdale; Dominic Nelson; Simon Gravel; Jerome Kelleher

    Simulation plays a central role in population genomics studies. Recent years have seen rapid improvements in software efficiency that make it possible to simulate large genomic regions for many individuals sampled from large numbers of populations. As the complexity of the demographic models we study grows, however, there is an ever-increasing opportunity to introduce bugs in their implementation.

    更新日期:2020-10-02
  • Roadmap for Establishing Large-Scale Genomic Medicine Initiatives in Low- and Middle-Income Countries
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-10-01
    George P. Patrinos; Emmanouil Pasparakis; Erasmia Koiliari; Alexandre C. Pereira; Tábita Hünemeier; Lygia V. Pereira; Christina Mitropoulou

    In the post-genomic era, genomic medicine interventions as a key component of personalized medicine and tailored-made health care are greatly anticipated following recent scientific and technological advances. Indeed, large-scale sequencing efforts that explore human genomic variation have been initiated in several, mostly developed, countries across the globe, such as the United States, the United

    更新日期:2020-10-02
  • Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-26
    Tamara S Roman,Stephanie B Crowley,Myra I Roche,Ann Katherine M Foreman,Julianne M O'Daniel,Bryce A Seifert,Kristy Lee,Alicia Brandt,Chelsea Gustafson,Daniela M DeCristo,Natasha T Strande,Lori Ramkissoon,Laura V Milko,Phillips Owen,Sayanty Roy,Mai Xiong,Ryan S Paquin,Rita M Butterfield,Megan A Lewis,Katherine J Souris,Donald B Bailey,Christine Rini,Jessica K Booker,Bradford C Powell,Karen E Weck,Cynthia

    Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the

    更新日期:2020-10-02
  • Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Kristi Krebs,Jonas Bovijn,Neil Zheng,Maarja Lepamets,Jenny C Censin,Tuuli Jürgenson,Dage Särg,Erik Abner,Triin Laisk,Yang Luo,Line Skotte,Frank Geller,Bjarke Feenstra,Wei Wang,Adam Auton,,Soumya Raychaudhuri,Tõnu Esko,Andres Metspalu,Sven Laur,Dan M Roden,Wei-Qi Wei,Michael V Holmes,Cecilia M Lindgren,Elizabeth J Phillips,Reedik Mägi,Lili Milani,João Fadista

    Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000

    更新日期:2020-10-02
  • Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Michelle R Jones,Pei-Chen Peng,Simon G Coetzee,Jonathan Tyrer,Alberto Luiz P Reyes,Rosario I Corona,Brian Davis,Stephanie Chen,Felipe Dezem,Ji-Heui Seo,Siddartha Kar,Eileen Dareng,,Benjamin P Berman,Matthew L Freedman,Jasmine T Plummer,Kate Lawrenson,Paul Pharoah,Dennis J Hazelett,Simon A Gayther

    Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this

    更新日期:2020-10-02
  • Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Cindy Im,Na Qin,Zhaoming Wang,Weiyu Qiu,Carrie R Howell,Yadav Sapkota,Wonjong Moon,Wassim Chemaitilly,Todd M Gibson,Daniel A Mulrooney,Kirsten K Ness,Carmen L Wilson,Lindsay M Morton,Gregory T Armstrong,Smita Bhatia,Jinghui Zhang,Melissa M Hudson,Leslie L Robison,Yutaka Yasui

    With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in

    更新日期:2020-10-02
  • A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-15
    Paras Garg,Bharati Jadhav,Oscar L Rodriguez,Nihir Patel,Alejandro Martin-Trujillo,Miten Jain,Sofie Metsu,Hugh Olsen,Benedict Paten,Beate Ritz,R Frank Kooy,Jozef Gecz,Andrew J Sharp

    There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals

    更新日期:2020-10-02
  • Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-09
    Sara Althari,Laeya A Najmi,Amanda J Bennett,Ingvild Aukrust,Jana K Rundle,Kevin Colclough,Janne Molnes,Alba Kaci,Sameena Nawaz,Timme van der Lugt,Neelam Hassanali,Anubha Mahajan,Anders Molven,Sian Ellard,Mark I McCarthy,Lise Bjørkhaug,Pål Rasmus Njølstad,Anna L Gloyn

    Exome sequencing in diabetes presents a diagnostic challenge because depending on frequency, functional impact, and genomic and environmental contexts, HNF1A variants can cause maturity-onset diabetes of the young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset

    更新日期:2020-10-02
  • Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-26
    Peter D Galer,Shiva Ganesan,David Lewis-Smith,Sarah E McKeown,Manuela Pendziwiat,Katherine L Helbig,Colin A Ellis,Annika Rademacher,Lacey Smith,Annapurna Poduri,Simone Seiffert,Sarah von Spiczak,Hiltrud Muhle,Andreas van Baalen,,,,,Rhys H Thomas,Roland Krause,Yvonne Weber,Ingo Helbig

    More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed

    更新日期:2020-10-02
  • Inferring Gene-by-Environment Interactions with a Bayesian Whole-Genome Regression Model.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Matthew Kerin,Jonathan Marchini

    The contribution of gene-by-environment (GxE) interactions for many human traits and diseases is poorly characterized. We propose a Bayesian whole-genome regression model for joint modeling of main genetic effects and GxE interactions in large-scale datasets, such as the UK Biobank, where many environmental variables have been measured. The method is called LEMMA (Linear Environment Mixed Model Analysis)

    更新日期:2020-10-02
  • Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-21
    Justin M Luningham,Junyu Chen,Shizhen Tang,Philip L De Jager,David A Bennett,Aron S Buchman,Jingjing Yang

    Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that

    更新日期:2020-10-02
  • Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-04
    Dervla M Connaughton,Rufeng Dai,Danielle J Owen,Jonathan Marquez,Nina Mann,Adda L Graham-Paquin,Makiko Nakayama,Etienne Coyaud,Estelle M N Laurent,Jonathan R St-Germain,Lot Snijders Blok,Arianna Vino,Verena Klämbt,Konstantin Deutsch,Chen-Han Wilfred Wu,Caroline M Kolvenbach,Franziska Kause,Isabel Ottlewski,Ronen Schneider,Thomas M Kitzler,Amar J Majmundar,Florian Buerger,Ana C Onuchic-Whitford,Mao

    Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a

    更新日期:2020-10-02
  • Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Anna Middleton,Richard Milne,Mohamed A Almarri,Shamim Anwer,Jerome Atutornu,Elena E Baranova,Paul Bevan,Maria Cerezo,Yali Cong,Christine Critchley,Josepine Fernow,Peter Goodhand,Qurratulain Hasan,Aiko Hibino,Gry Houeland,Heidi C Howard,S Zakir Hussain,Charlotta Ingvoldstad Malmgren,Vera L Izhevskaya,Aleksandra Jędrzejak,Cao Jinhong,Megumi Kimura,Erika Kleiderman,Brandi Leach,Keying Liu,Deborah Mascalzoni

    Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do

    更新日期:2020-10-02
  • De Novo Variants in LMNB1 Cause Pronounced Syndromic Microcephaly and Disruption of Nuclear Envelope Integrity.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-09
    Francesca Cristofoli,Tonya Moss,Hannah W Moore,Koen Devriendt,Heather Flanagan-Steet,Melanie May,Julie Jones,Filip Roelens,Carmen Fons,Anna Fernandez,Loreto Martorell,Angelo Selicorni,Silvia Maitz,Giuseppina Vitiello,Gerd Van der Hoeven,Steven A Skinner,Mathieu Bollen,Joris R Vermeesch,Richard Steet,Hilde Van Esch

    Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with

    更新日期:2020-10-02
  • De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-15
    Natalia Mendoza-Ferreira,Mert Karakaya,Nur Cengiz,Danique Beijer,Karlla W Brigatti,Claudia Gonzaga-Jauregui,Nico Fuhrmann,Irmgard Hölker,Maximilian P Thelen,Sebastian Zetzsche,Roman Rombo,Erik G Puffenberger,Peter De Jonghe,Tine Deconinck,Stephan Zuchner,Kevin A Strauss,Vincent Carson,Bertold Schrank,Gilbert Wunderlich,Jonathan Baets,Brunhilde Wirth

    Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant

    更新日期:2020-10-02
  • eQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-31
    Jonathan Beesley,Haran Sivakumaran,Mahdi Moradi Marjaneh,Wei Shi,Kristine M Hillman,Susanne Kaufmann,Nehal Hussein,Siddhartha Kar,Luize G Lima,Sunyoung Ham,Andreas Möller,Georgia Chenevix-Trench,Stacey L Edwards,Juliet D French

    Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression

    更新日期:2020-10-02
  • Advancing Diverse Participation in Research with Special Consideration for Vulnerable Populations.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03

    It is imperative for participation in genetics and genomics research to reflect humanity’s diversity so that all people can enjoy its benefits. This will take a concerted effort by the research community and must include greater engagement with individuals and communities underrepresented in research. In engaging with vulnerable populations, it is essential that researchers guard against harm resulting

    更新日期:2020-09-03
  • The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-12
    Marissa LoPresti,David B Beck,Priya Duggal,Derek A T Cummings,Benjamin D Solomon

    The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies

    更新日期:2020-09-03
  • Interpretable Clinical Genomics with a Likelihood Ratio Paradigm.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-04
    Peter N Robinson,Vida Ravanmehr,Julius O B Jacobsen,Daniel Danis,Xingmin Aaron Zhang,Leigh C Carmody,Michael A Gargano,Courtney L Thaxton,,Guy Karlebach,Justin Reese,Manuel Holtgrewe,Sebastian Köhler,Julie A McMurry,Melissa A Haendel,Damian Smedley

    Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide

    更新日期:2020-09-03
  • Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Allison Meisner,Prosenjit Kundu,Yan Dora Zhang,Lauren V Lan,Sungwon Kim,Disha Ghandwani,Parichoy Pal Choudhury,Sonja I Berndt,Neal D Freedman,Montserrat Garcia-Closas,Nilanjan Chatterjee

    While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated

    更新日期:2020-09-03
  • Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Minta Thomas,Lori C Sakoda,Michael Hoffmeister,Elisabeth A Rosenthal,Jeffrey K Lee,Franzel J B van Duijnhoven,Elizabeth A Platz,Anna H Wu,Christopher H Dampier,Albert de la Chapelle,Alicja Wolk,Amit D Joshi,Andrea Burnett-Hartman,Andrea Gsur,Annika Lindblom,Antoni Castells,Aung Ko Win,Bahram Namjou,Bethany Van Guelpen,Catherine M Tangen,Qianchuan He,Christopher I Li,Clemens Schafmayer,Corinne E Joshu

    Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of

    更新日期:2020-09-03
  • Evolution of a Human-Specific Tandem Repeat Associated with ALS.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-03
    Meredith M Course,Kathryn Gudsnuk,Samuel N Smukowski,Kosuke Winston,Nitin Desai,Jay P Ross,Arvis Sulovari,Cynthia V Bourassa,Dan Spiegelman,Julien Couthouis,Chang-En Yu,Debby W Tsuang,Suman Jayadev,Mark A Kay,Aaron D Gitler,Nicolas Dupre,Evan E Eichler,Patrick A Dion,Guy A Rouleau,Paul N Valdmanis

    Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater

    更新日期:2020-09-03
  • Detecting Allele-Specific Alternative Splicing from Population-Scale RNA-Seq Data.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-10
    Levon Demirdjian,Yungang Xu,Emad Bahrami-Samani,Yang Pan,Shayna Stein,Zhijie Xie,Eddie Park,Ying Nian Wu,Yi Xing

    RNA sequencing (RNA-seq) is a powerful technology for studying human transcriptome variation. We introduce PAIRADISE (Paired Replicate Analysis of Allelic Differential Splicing Events), a method for detecting allele-specific alternative splicing (ASAS) from RNA-seq data. Unlike conventional approaches that detect ASAS events one sample at a time, PAIRADISE aggregates ASAS signals across multiple individuals

    更新日期:2020-09-03
  • High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-10
    Julius Mulindwa,Harry Noyes,Hamidou Ilboudo,Luca Pagani,Oscar Nyangiri,Magambo Phillip Kimuda,Bernardin Ahouty,Olivier Fataki Asina,Elvis Ofon,Kelita Kamoto,Justin Windingoudi Kabore,Mathurin Koffi,Dieudonne Mumba Ngoyi,Gustave Simo,John Chisi,Issa Sidibe,John Enyaru,Martin Simuunza,Pius Alibu,Vincent Jamonneau,Mamadou Camara,Andy Tait,Neil Hall,Bruno Bucheton,Annette MacLeod,Christiane Hertz-Fowler

    Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population

    更新日期:2020-09-03
  • Promoter CpG Density Predicts Downstream Gene Loss-of-Function Intolerance.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-14
    Leandros Boukas,Hans T Bjornsson,Kasper D Hansen

    The aggregation and joint analysis of large numbers of exome sequences has recently made it possible to derive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich promoters (top 10% CpG density) have a 67

    更新日期:2020-09-03
  • Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-27
    Marialetizia Motta,Luca Pannone,Francesca Pantaleoni,Gianfranco Bocchinfuso,Francesca Clementina Radio,Serena Cecchetti,Andrea Ciolfi,Martina Di Rocco,Mariet W Elting,Eva H Brilstra,Stefania Boni,Laura Mazzanti,Federica Tamburrino,Larry Walsh,Katelyn Payne,Alberto Fernández-Jaén,Mythily Ganapathi,Wendy K Chung,Dorothy K Grange,Ashita Dave-Wala,Shalini C Reshmi,Dennis W Bartholomew,Danielle Mouhlas

    Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in

    更新日期:2020-09-03