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  • Reproductive Choice and Research
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-04-02

    Laws should recognize the reproductive rights of women—including the option to terminate a pregnancy—and their ability to advance medical research through the donation of fetal tissue for research.

    更新日期:2020-04-03
  • Co-localization between Sequence Constraint and Epigenomic Information Improves Interpretation of Whole-Genome Sequencing Data
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-04-02
    Danqing Xu; Chen Wang; Krzysztof Kiryluk; Joseph D. Buxbaum; Iuliana Ionita-Laza

    The identification of functional regions in the noncoding human genome is difficult but critical in order to gain understanding of the role noncoding variation plays in gene regulation in human health and disease. We describe here a co-localization approach that aims to identify constrained sequences that co-localize with tissue- or cell-type-specific regulatory regions, and we show that the resulting

    更新日期:2020-04-03
  • Genotyping Array Design and Data Quality Control in the Million Veteran Program
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-04-02
    Haley Hunter-Zinck; Yunling Shi; Man Li; Bryan R. Gorman; Sun-Gou Ji; Ning Sun; Teresa Webster; Andrew Liem; Paul Hsieh; Poornima Devineni; Purushotham Karnam; Xin Gong; Lakshmi Radhakrishnan; Jeanette Schmidt; Themistocles L. Assimes; Jie Huang; Cuiping Pan; Donald Humphries; Saiju Pyarajan

    The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision

    更新日期:2020-04-03
  • DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-04-02
    Sanaa Choufani; William T. Gibson; Andrei L. Turinsky; Brian H.Y. Chung; Tianren Wang; Kopal Garg; Alessandro Vitriolo; Ana S.A. Cohen; Sharri Cyrus; Sarah Goodman; Eric Chater-Diehl; Jack Brzezinski; Michael Brudno; Luk Ho Ming; Susan M. White; Sally Ann Lynch; Carol Clericuzio; I. Karen Temple; Rosanna Weksberg

    Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive

    更新日期:2020-04-03
  • Genetic Architecture of Gene Expression in European and African Americans: An eQTL Mapping Study in GENOA
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-26
    Lulu Shang; Jennifer A. Smith; Wei Zhao; Minjung Kho; Stephen T. Turner; Thomas H. Mosley; Sharon L.R. Kardia; Xiang Zhou

    Most existing expression quantitative trait locus (eQTL) mapping studies have been focused on individuals of European ancestry and are underrepresented in other populations including populations with African ancestry. Lack of large-scale well-powered eQTL mapping studies in populations with African ancestry can both impede the dissemination of eQTL mapping results that would otherwise benefit individuals

    更新日期:2020-03-27
  • Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-26
    Laura Girardi; Munevver Serdarogullari; Cristina Patassini; Maurizio Poli; Marco Fabiani; Silvia Caroselli; Onder Coban; Necati Findikli; Fazilet Kubra Boynukalin; Mustafa Bahceci; Rupali Chopra; Rita Canipari; Danilo Cimadomo; Laura Rienzi; Filippo Ubaldi; Eva Hoffmann; Carmen Rubio; Carlos Simon; Antonio Capalbo

    Despite next-generation sequencing, which now allows for the accurate detection of segmental aneuploidies from in vitro fertilization embryo biopsies, the origin and characteristics of these aneuploidies are still relatively unknown. Using a multifocal biopsy approach (four trophectoderms [TEs] and one inner cell mass [ICM] analyzed per blastocyst; n = 390), we determine the origin of the aneuploidy

    更新日期:2020-03-27
  • Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-26
    Thi Tuyet Mai Nguyen; Yoshiko Murakami; Sabrina Mobilio; Marcello Niceta; Giuseppe Zampino; Christophe Philippe; Sébastien Moutton; Maha S. Zaki; Kiely N. James; Damir Musaev; Weiyi Mu; Kristin Baranano; Jessica R. Nance; Jill A. Rosenfeld; Nancy Braverman; Andrea Ciolfi; Francisca Millan; Richard E. Person; Philippe M. Campeau

    Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10

    更新日期:2020-03-27
  • Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-26
    Tiong Yang Tan; Jiří Sedmík; Mark P. Fitzgerald; Rivka Sukenik Halevy; Liam P. Keegan; Ingo Helbig; Lina Basel-Salmon; Lior Cohen; Rachel Straussberg; Wendy K. Chung; Mayada Helal; Reza Maroofian; Henry Houlden; Jane Juusola; Simon Sadedin; Lynn Pais; Katherine B. Howell; Susan M. White; Mary A. O’Connell

    The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded

    更新日期:2020-03-27
  • Rapid, Phase-free Detection of Long Identical by Descent Segments Enables Effective Relationship Classification
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-19
    Daniel N. Seidman; Sushila A. Shenoy; Minsoo Kim; Ramya Babu; Ian G. Woods; Thomas D. Dyer; Donna M. Lehman; Joanne E. Curran; Ravindranath Duggirala; John Blangero; Amy L. Williams

    Identical by descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions

    更新日期:2020-03-20
  • De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-19
    Dongxue Mao; Chloe M. Reuter; Maura R.Z. Ruzhnikov; Anita E. Beck; Emily G. Farrow; Lisa T. Emrick; Jill A. Rosenfeld; Katherine M. Mackenzie; Laurie Robak; Matthew T. Wheeler; Lindsay C. Burrage; Mahim Jain; Pengfei Liu; Daniel Calame; Sébastien Küry; Martin Sillesen; Klaus Schmitz-Abe; Davide Tonduti; Hsiao-Tuan Chao

    EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious

    更新日期:2020-03-20
  • Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-19
    Xiaomin Dong; Natalie B. Tan; Katherine B. Howell; Sabina Barresi; Jeremy L. Freeman; Davide Vecchio; Maria Piccione; Francesca Clementina Radio; Daniel Calame; Shan Zong; Stefanie Eggers; Ingrid E. Scheffer; Tiong Y. Tan; Nicole J. Van Bergen; Marco Tartaglia; John Christodoulou; Susan M. White

    Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals

    更新日期:2020-03-20
  • De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-19
    Francesca Mattioli; Gaelle Hayot; Nathalie Drouot; Bertrand Isidor; Jérémie Courraud; Maria-Victoria Hinckelmann; Frederic Tran Mau-Them; Chantal Sellier; Alica Goldman; Aida Telegrafi; Alicia Boughton; Candace Gamble; Sebastien Moutton; Angélique Quartier; Nolwenn Jean; Paul Van Ness; Sarah Grotto; Sophie Nambot; Amélie Piton

    The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability

    更新日期:2020-03-20
  • De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-12
    Kohei Hamanaka; Eri Imagawa; Eriko Koshimizu; Satoko Miyatake; Jun Tohyama; Takanori Yamagata; Akihiko Miyauchi; Nina Ekhilevitch; Fumio Nakamura; Takeshi Kawashima; Yoshio Goshima; Ahmad Rithauddin Mohamed; Gaik-Siew Ch'ng; Atsushi Fujita; Yoshiteru Azuma; Ken Yasuda; Shintaro Imamura; Mitsuko Nakashima; Naomichi Matsumoto

    De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(−) region]. Such variants can have dominant-negative

    更新日期:2020-03-12
  • A Fast and Simple Method for Detecting Identity by Descent Segments in Large-Scale Data
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-12
    Ying Zhou; Sharon R. Browning; Brian L. Browning

    Segments of identity by descent (IBD) are used in many genetic analyses. We present a method for detecting identical-by-descent haplotype segments in phased genotype data. Our method, called hap-IBD, combines a compressed representation of haplotype data, the positional Burrows-Wheeler transform, and multi-threaded execution to produce very fast analysis times. An attractive feature of hap-IBD is its

    更新日期:2020-03-12
  • Population Histories of the United States Revealed through Fine-Scale Migration and Haplotype Analysis
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-05
    Chengzhen L. Dai; Mohammad M. Vazifeh; Chen-Hsiang Yeang; Remi Tachet; R. Spencer Wells; Miguel G. Vilar; Mark J. Daly; Carlo Ratti; Alicia R. Martin

    The population of the United States is shaped by centuries of migration, isolation, growth, and admixture between ancestors of global origins. Here, we assemble a comprehensive view of recent population history by studying the ancestry and population structure of more than 32,000 individuals in the US using genetic, ancestral birth origin, and geographic data from the National Geographic Genographic

    更新日期:2020-03-05
  • Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-03-05
    Lucia V. Schottlaender; Rosella Abeti; Zane Jaunmuktane; Carol Macmillan; Viorica Chelban; Benjamin O’Callaghan; John McKinley; Reza Maroofian; Stephanie Efthymiou; Alkyoni Athanasiou-Fragkouli; Raeburn Forbes; Marc P.M. Soutar; John H. Livingston; Bernardett Kalmar; Orlando Swayne; Gary Hotton

    Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting

    更新日期:2020-03-05
  • Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-26
    Erfan Aref-Eshghi,Jennifer Kerkhof,Victor P Pedro,,Mouna Barat-Houari,Nathalie Ruiz-Pallares,Jean-Christophe Andrau,Didier Lacombe,Julien Van-Gils,Patricia Fergelot,Christèle Dubourg,Valerie Cormier-Daire,Sophie Rondeau,François Lecoquierre,Pascale Saugier-Veber,Gaël Nicolas,Gaetan Lesca,Nicolas Chatron,Damien Sanlaville,Antonio Vitobello,Laurence Faivre,Christel Thauvin-Robinet,Frederic Laumonnier

    Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation

    更新日期:2020-02-28
  • Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-25
    Sónia Barbosa,Stephanie Greville-Heygate,Maxime Bonnet,Annie Godwin,Christine Fagotto-Kaufmann,Andrey V Kajava,Damien Laouteouet,Rebecca Mawby,Htoo Aung Wai,Alexander J M Dingemans,Jayne Hehir-Kwa,Marjorlaine Willems,Yline Capri,Sarju G Mehta,Helen Cox,David Goudie,Fleur Vansenne,Peter Turnpenny,Marie Vincent,Benjamin Cogné,Gaëtan Lesca,Jozef Hertecant,Diana Rodriguez,Boris Keren,Lydie Burglen,Marion

    The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report

    更新日期:2020-02-28
  • De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-25
    Maria J Nabais Sá,Geniver El Tekle,Arjan P M de Brouwer,Sarah L Sawyer,Daniela Del Gaudio,Michael J Parker,Farah Kanani,Marie-José H van den Boogaard,Koen van Gassen,Margot I Van Allen,Klaas Wierenga,Gabriela Purcarin,Ellen Roy Elias,Amber Begtrup,Jennifer Keller-Ramey,Tiziano Bernasocchi,Laurens van de Wiel,Christian Gilissen,Hanka Venselaar,Rolph Pfundt,Lisenka E L M Vissers,Jean-Philippe P Theurillat

    Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies

    更新日期:2020-02-28
  • Genome-Wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-20
    Chen Li,Svetlana Stoma,Luca A Lotta,Sophie Warner,Eva Albrecht,Alessandra Allione,Pascal P Arp,Linda Broer,Jessica L Buxton,Alexessander Da Silva Couto Alves,Joris Deelen,Iryna O Fedko,Scott D Gordon,Tao Jiang,Robert Karlsson,Nicola Kerrison,Taylor K Loe,Massimo Mangino,Yuri Milaneschi,Benjamin Miraglio,Natalia Pervjakova,Alessia Russo,Ida Surakka,Ashley van der Spek,Josine E Verhoeven,Najaf Amin,Marian

    Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting

    更新日期:2020-02-27
  • Advocating for Genetics and Genomics Research to Policymakers
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-06

    It is essential for the genetics and genomics community to communicate the exciting progress in our field to policymakers. This outreach is key for bolstering governmental support for research and ensuring a favorable policy environment for scientists. To advance fundamental discoveries, clinical advances, and the economy, policymakers need to know the importance of genetic research and our commitment

    更新日期:2020-02-20
  • The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-06
    Kym M Boycott,Philippe M Campeau,Heather E Howley,Paul Pavlidis,Sanja Rogic,Christine Oriel,Jason N Berman,Robert M Hamilton,Geoffrey G Hicks,Howard D Lipshitz,Jean-Yves Masson,Eric A Shoubridge,Anne Junker,Michel R Leroux,Christopher R McMaster,Jaques L Michaud,Stuart E Turvey,David Dyment,A Micheil Innes,Clara D van Karnebeek,Anna Lehman,Ronald D Cohn,Ian M MacDonald,Richard A Rachubinski,Patrick

    Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address

    更新日期:2020-02-20
  • Enhancer Domains Predict Gene Pathogenicity and Inform Gene Discovery in Complex Disease.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-06
    Xinchen Wang,David B Goldstein

    Non-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the sizes and number of enhancers linked to a gene reflect its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and they are buffered against the effects of disruptive

    更新日期:2020-02-20
  • Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-17
    Emily Jamieson,Roxanna Korologou-Linden,Robyn E Wootton,Anna L Guyatt,Thomas Battram,Kimberley Burrows,Tom R Gaunt,Martin D Tobin,Marcus Munafò,George Davey Smith,Kate Tilling,Caroline Relton,Tom G Richardson,Rebecca C Richmond

    Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used

    更新日期:2020-02-20
  • Influence of Genetic Ancestry on Human Serum Proteome.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-07
    Jennifer Sjaarda,Hertzel C Gerstein,Zoltan Kutalik,Pedrum Mohammadi-Shemirani,Marie Pigeyre,Sibylle Hess,Guillaume Paré

    Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within

    更新日期:2020-02-20
  • Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-02-05
    Despoina Manousaki,Ruth Mitchell,Tom Dudding,Simon Haworth,Adil Harroud,Vincenzo Forgetta,Rupal L Shah,Jian'an Luan,Claudia Langenberg,Nicholas J Timpson,J Brent Richards

    We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and

    更新日期:2020-02-20
  • The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Diana S C Han,Meng Ni,Rebecca W Y Chan,Vicken W H Chan,Kathy O Lui,Rossa W K Chiu,Y M Dennis Lo

    Cell-free DNA (cf.DNA) is a powerful noninvasive biomarker for cancer and prenatal testing, and it circulates in plasma as short fragments. To elucidate the biology of cf.DNA fragmentation, we explored the roles of deoxyribonuclease 1 (DNASE1), deoxyribonuclease 1 like 3 (DNASE1L3), and DNA fragmentation factor subunit beta (DFFB) with mice deficient in each of these nucleases. By analyzing the ends

    更新日期:2020-01-31
  • Allele-Specific QTL Fine Mapping with PLASMA.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Austin T Wang,Anamay Shetty,Edward O'Connor,Connor Bell,Mark M Pomerantz,Matthew L Freedman,Alexander Gusev

    Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are concordant with traditional QTLs but typically less susceptible to te

    更新日期:2020-01-31
  • Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Sharon A Savage,Mathias Viard,Colm O'hUigin,Weiyin Zhou,Meredith Yeager,Shengchao Alfred Li,Tao Wang,Veron Ramsuran,Nicolas Vince,Aurelie Vogt,Belynda Hicks,Laurie Burdett,Charles Chung,Michael Dean,Kelvin C de Andrade,Neal D Freedman,Sonja I Berndt,Nathaniel Rothman,Qing Lan,James R Cerhan,Susan L Slager,Yawei Zhang,Lauren R Teras,Michael Haagenson,Stephen J Chanock,Stephen R Spellman,Youjin Wang

    Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation

    更新日期:2020-01-31
  • Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Saskia B Wortmann,Brigitte Meunier,Lamia Mestek-Boukhibar,Florence van den Broek,Elaina M Maldonado,Emma Clement,Daniel Weghuber,Johannes Spenger,Zdenek Jaros,Fatma Taha,Wyatt W Yue,Simon J Heales,James E Davison,Johannes A Mayr,Shamima Rahman

    We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation

    更新日期:2020-01-31
  • Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Matias Wagner,Yuliya Skorobogatko,Ben Pode-Shakked,Cynthia M Powell,Bader Alhaddad,Annette Seibt,Ortal Barel,Gali Heimer,Chen Hoffmann,Laurie A Demmer,Yezmin Perilla-Young,Marc Remke,Dagmar Wieczorek,Tharsini Navaratnarajah,Peter Lichtner,Dirk Klee,Hanan E Shamseldin,Fuad Al Mutairi,Ertan Mayatepek,Tim Strom,Thomas Meitinger,Fowzan S Alkuraya,Yair Anikster,Alan R Saltiel,Felix Distelmaier

    Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase

    更新日期:2020-01-31
  • Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-30
    Adam C Gunning,Klaudia Strucinska,Mikel Muñoz Oreja,Andrew Parrish,Richard Caswell,Karen L Stals,Romina Durigon,Karina Durlacher-Betzer,Mitchell H Cunningham,Christopher M Grochowski,Julia Baptista,Carolyn Tysoe,Emma Baple,Nayana Lahiri,Tessa Homfray,Ingrid Scurr,Catherine Armstrong,John Dean,Uxoa Fernandez Pelayo,Aleck W E Jones,Robert W Taylor,Vinod K Misra,Wan Hee Yoon,Caroline F Wright,James R

    Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom

    更新日期:2020-01-31
  • A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-23
    Anne Ndungu,Anthony Payne,Jason M Torres,Martijn van de Bunt,Mark I McCarthy

    There is particular interest in transcriptome-wide association studies (TWAS) gene-level tests based on multi-SNP predictive models of gene expression-for identifying causal genes at loci associated with complex traits. However, interpretation of TWAS associations may be complicated by divergent effects of model SNPs on phenotype and gene expression. We developed an iterative modeling scheme for obtaining

    更新日期:2020-01-23
  • TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-23
    Lucie Thomas,Khaled Bouhouche,Marjorie Whitfield,Guillaume Thouvenin,Andre Coste,Bruno Louis,Claire Szymanski,Emilie Bequignon,Jean-François Papon,Manon Castelli,Michel Lemullois,Xavier Dhalluin,Valérie Drouin-Garraud,Guy Montantin,Sylvie Tissier,Philippe Duquesnoy,Bruno Copin,Florence Dastot,Sandrine Couvet,Anne-Laure Barbotin,Catherine Faucon,Isabelle Honore,Bernard Maitre,Nicole Beydon,Aline Tamalet

    Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella

    更新日期:2020-01-23
  • Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-09
    David B Beck,Ana Petracovici,Chongsheng He,Hannah W Moore,Raymond J Louie,Muhammad Ansar,Sofia Douzgou,Sivagamy Sithambaram,Trudie Cottrell,Regie Lyn P Santos-Cortez,Eloise J Prijoles,Renee Bend,Boris Keren,Cyril Mignot,Marie-Christine Nougues,Katrin Õunap,Tiia Reimand,Sander Pajusalu,Muhammad Zahid,Muhammad Arif Nadeem Saqib,Julien Buratti,Eleanor G Seaby,Kirsty McWalter,Aida Telegrafi,Dustin Baldridge

    Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has

    更新日期:2020-01-09
  • A Robust Method Uncovers Significant Context-Specific Heritability in Diverse Complex Traits.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2020-01-02
    Andy Dahl,Khiem Nguyen,Na Cai,Michael J Gandal,Jonathan Flint,Noah Zaitlen

    Gene-environment interactions (GxE) can be fundamental in applications ranging from functional genomics to precision medicine and is a conjectured source of substantial heritability. However, unbiased methods to profile GxE genome-wide are nascent and, as we show, cannot accommodate general environment variables, modest sample sizes, heterogeneous noise, and binary traits. To address this gap, we propose

    更新日期:2020-01-02
  • Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-26
    Andrea Messina,Kristiina Pulli,Sara Santini,James Acierno,Johanna Känsäkoski,Daniele Cassatella,Cheng Xu,Filippo Casoni,Samuel A Malone,Gaetan Ternier,Daniele Conte,Yisrael Sidis,Johanna Tommiska,Kirsi Vaaralahti,Andrew Dwyer,Yoav Gothilf,Giorgio R Merlo,Federico Santoni,Nicolas J Niederländer,Paolo Giacobini,Taneli Raivio,Nelly Pitteloud

    Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or

    更新日期:2019-12-27
  • Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-26
    Joel J Hughes,Ebba Alkhunaizi,Paul Kruszka,Louise C Pyle,Dorothy K Grange,Seth I Berger,Katelyn K Payne,Diane Masser-Frye,Tommy Hu,Michelle R Christie,Nancy J Clegg,Joshua L Everson,Ariel F Martinez,Laurence E Walsh,Emma Bedoukian,Marilyn C Jones,Catharine Jean Harris,Korbinian M Riedhammer,Daniela Choukair,Patricia Y Fechner,Meilan M Rutter,Sophia B Hufnagel,Maian Roifman,Gad B Kletter,Emmanuele Delot

    In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration

    更新日期:2019-12-27
  • Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-26
    Mirjana Gusic,Gudrun Schottmann,René G Feichtinger,Chen Du,Caroline Scholz,Matias Wagner,Johannes A Mayr,Chae-Young Lee,Vicente A Yépez,Norbert Lorenz,Susanne Morales-Gonzalez,Daan M Panneman,Agnès Rötig,Richard J T Rodenburg,Saskia B Wortmann,Holger Prokisch,Markus Schuelke

    Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene

    更新日期:2019-12-27
  • Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-26
    Laura M Raffield,Apoorva K Iyengar,Biqi Wang,Sheila M Gaynor,Cassandra N Spracklen,Xue Zhong,Madeline H Kowalski,Shabnam Salimi,Linda M Polfus,Emelia J Benjamin,Joshua C Bis,Russell Bowler,Brian E Cade,Won Jung Choi,Alejandro P Comellas,Adolfo Correa,Pedro Cruz,Harsha Doddapaneni,Peter Durda,Stephanie M Gogarten,Deepti Jain,Ryan W Kim,Brian G Kral,Leslie A Lange,Martin G Larson,Cecelia Laurie,Jiwon

    Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals

    更新日期:2019-12-27
  • Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-26
    Justin O Szot,Carla Campagnolo,Ye Cao,Kavitha R Iyer,Hartmut Cuny,Thomas Drysdale,Josue A Flores-Daboub,Weimin Bi,Lauren Westerfield,Pengfei Liu,Tse Ngong Leung,Kwong Wai Choy,Gavin Chapman,Rui Xiao,Victoria M Siu,Sally L Dunwoodie

    Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence

    更新日期:2019-12-27
  • Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-20
    Yingjie Zhao,Alexander Diacou,H Richard Johnston,Fadi I Musfee,Donna M McDonald-McGinn,Daniel McGinn,T Blaine Crowley,Gabriela M Repetto,Ann Swillen,Jeroen Breckpot,Joris R Vermeesch,Wendy R Kates,M Cristina Digilio,Marta Unolt,Bruno Marino,Maria Pontillo,Marco Armando,Fabio Di Fabio,Stefano Vicari,Marianne van den Bree,Hayley Moss,Michael J Owen,Kieran C Murphy,Clodagh M Murphy,Declan Murphy,Kelly

    The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region

    更新日期:2019-12-20
  • Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-19
    Charlotte L Alston,Mike T Veling,Juliana Heidler,Lucie S Taylor,Joseph T Alaimo,Andrew Y Sung,Langping He,Sila Hopton,Alexander Broomfield,Julija Pavaine,Jullianne Diaz,Eyby Leon,Philipp Wolf,Robert McFarland,Holger Prokisch,Saskia B Wortmann,Penelope E Bonnen,Ilka Wittig,David J Pagliarini,Robert W Taylor

    Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with

    更新日期:2019-12-19
  • SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-19
    Samantha L P Schilit,Shreya Menon,Corinna Friedrich,Tammy Kammin,Ellen Wilch,Carrie Hanscom,Sizun Jiang,Sabine Kliesch,Michael E Talkowski,Frank Tüttelmann,Amy J MacQueen,Cynthia C Morton

    Unexplained infertility affects 2%-3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject

    更新日期:2019-12-19
  • UK Biobank Whole-Exome Sequence Binary Phenome Analysis with Robust Region-Based Rare-Variant Test.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-19
    Zhangchen Zhao,Wenjian Bi,Wei Zhou,Peter VandeHaar,Lars G Fritsche,Seunggeun Lee

    In biobank data analysis, most binary phenotypes have unbalanced case-control ratios, and this can cause inflation of type I error rates. Recently, a saddle point approximation (SPA) based single-variant test has been developed to provide an accurate and scalable method to test for associations of such phenotypes. For gene- or region-based multiple-variant tests, a few methods exist that can adjust

    更新日期:2019-12-19
  • Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-12
    Noriko Miyake,Hidehisa Takahashi,Kazuyuki Nakamura,Bertrand Isidor,Yoko Hiraki,Eriko Koshimizu,Masaaki Shiina,Kazunori Sasaki,Hidefumi Suzuki,Ryota Abe,Yayoi Kimura,Tomoko Akiyama,Shin-Ichi Tomizawa,Tomonori Hirose,Kohei Hamanaka,Satoko Miyatake,Satomi Mitsuhashi,Takeshi Mizuguchi,Atsushi Takata,Kazuyuki Obo,Mitsuhiro Kato,Kazuhiro Ogata,Naomichi Matsumoto

    MN1 was originally identified as a tumor-suppressor gene. Knockout mouse studies have suggested that Mn1 is associated with craniofacial development. However, no MN1-related phenotypes have been established in humans. Here, we report on three individuals who have de novo MN1 variants that lead to a protein lacking the carboxyl (C) terminus and who presented with severe developmental delay, craniofacial

    更新日期:2019-12-13
  • Identification of African-Specific Admixture between Modern and Archaic Humans.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-05
    Jeffrey D Wall,Aakrosh Ratan,Eric Stawiski,

    Recent work has demonstrated that two archaic human groups (Neanderthals and Denisovans) interbred with modern humans and contributed to the contemporary human gene pool. These findings relied on the availability of high-coverage genomes from both Neanderthals and Denisovans. Here we search for evidence of archaic admixture from a worldwide panel of 1,667 individuals using an approach that does not

    更新日期:2019-12-05
  • Genomic Medicine Year in Review: 2019.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-12-05
    Teri A Manolio,Carol J Bult,Rex L Chisholm,Patricia A Deverka,Geoffrey S Ginsburg,Gail P Jarvik,Howard L McLeod,George A Mensah,Mary V Relling,Dan M Roden,Robb Rowley,Cecelia Tamburro,Marc S Williams,Eric D Green

    更新日期:2019-12-05
  • Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-27
    Tychele N Turner,Amy B Wilfert,Trygve E Bakken,Raphael A Bernier,Micah R Pepper,Zhancheng Zhang,Rebecca I Torene,Kyle Retterer,Evan E Eichler

    While 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

    更新日期:2019-11-28
  • Validation Studies for Single Circulating Trophoblast Genetic Testing as a Form of Noninvasive Prenatal Diagnosis.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-27
    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 Beaudet

    It 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

    更新日期:2019-11-28
  • Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-27
    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 Doummar,Boris Keren,Jane Juusola,Markus Grompe,Hugo J Bellen,Philippe M Campeau

    We 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

    更新日期:2019-11-28
  • Integrating Clinical Data and Imputed Transcriptome from GWAS to Uncover Complex Disease Subtypes: Applications in Psychiatry and Cardiology.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-27
    Liangying Yin,Carlos K L Chau,Pak-Chung Sham,Hon-Cheong So

    Classifying 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

    更新日期:2019-11-28
  • Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-21
    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 Reversade

    The 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

    更新日期:2019-11-22
  • Making the Most of Clumping and Thresholding for Polygenic Scores.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-21
    Florian Privé,Bjarni J Vilhjálmsson,Hugues Aschard,Michael G B Blum

    Polygenic 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

    更新日期:2019-11-22
  • Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-21
    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 Lionikas

    Muscle 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

    更新日期:2019-11-22
  • Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-14
    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 Favier,François Guillonneau,Marhaba Chaudhry,Zeinab Sakheli

    In 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

    更新日期:2019-11-14
  • Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-14
    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 Lv,Jinsong Li,Li Jin,Yunxia Cao,Feng Zhang

    As 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

    更新日期:2019-11-14
  • A Fast and Accurate Method for Genome-wide Scale Phenome-wide G × E Analysis and Its Application to UK Biobank.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-14
    Wenjian Bi,Zhangchen Zhao,Rounak Dey,Lars G Fritsche,Bhramar Mukherjee,Seunggeun Lee

    The 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

    更新日期:2019-11-14
  • TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-14
    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 Fawcett,Peter G J Nikkels,Aida Bertoli-Avella,Amal Al Hashem,Abdulmalik A Alwabel

    The 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

    更新日期:2019-11-14
  • TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.
    Am. J. Hum. Genet. (IF 9.924) Pub Date : 2019-11-07
    Karuna R M van der Meij,Erik A Sistermans,Merryn V E Macville,Servi J C Stevens,Caroline J Bax,Mireille N Bekker,Caterina M Bilardo,Elles M J Boon,Marjan Boter,Karin E M Diderich,Christine E M de Die-Smulders,Leonie K Duin,Brigitte H W Faas,Ilse Feenstra,Monique C Haak,Mariëtte J V Hoffer,Nicolette S den Hollander,Iris H I M Hollink,Fernanda S Jehee,Maarten F C M Knapen,Angelique J A Kooper,Irene M

    The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate

    更新日期:2019-11-08
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