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  • Management of Secondary Genomic Findings
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-02
    Alexander E. Katz; Robert L. Nussbaum; Benjamin D. Solomon; Heidi L. Rehm; Marc S. Williams; Leslie G. Biesecker

    Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ

    更新日期:2020-07-02
  • Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-29
    Zhihua Zhang,Bin Li,Jing Fu,Rong Li,Feiyang Diao,Caihong Li,Biaobang Chen,Jing Du,Zhou Zhou,Jian Mu,Zheng Yan,Ling Wu,Shuai Liu,Wenjing Wang,Lin Zhao,Jie Dong,Lin He,Xiaozhen Liang,Yanping Kuang,Xiaoxi Sun,Qing Sang,Lei Wang

    Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and

    更新日期:2020-07-02
  • Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-04
    Wei Zheng,Zhou Zhou,Qianqian Sha,Xiangli Niu,Xiaoxi Sun,Juanzi Shi,Lei Zhao,Shuoping Zhang,Jing Dai,Sufen Cai,Fei Meng,Liang Hu,Fei Gong,Xiaoran Li,Jing Fu,Rong Shi,Guangxiu Lu,Biaobang Chen,Hengyu Fan,Lei Wang,Ge Lin,Qing Sang

    Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern

    更新日期:2020-07-02
  • Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-03
    Huijun Wang,Aytaj Humbatova,Yuanxiang Liu,Wen Qin,Mingyang Lee,Nicole Cesarato,Fanny Kortüm,Sheetal Kumar,Maria Teresa Romano,Shangzhi Dai,Ran Mo,Sugirthan Sivalingam,Susanne Motameny,Yuan Wu,Xiaopeng Wang,Xinwu Niu,Songmei Geng,Dorothea Bornholdt,Peter M Kroisel,Gianluca Tadini,Scott D Walter,Fabian Hauck,Katta M Girisha,Anne-Marie Calza,Armand Bottani,Janine Altmüller,Andreas Buness,Shuxia Yang,Xiujuan

    IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant

    更新日期:2020-07-02
  • Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Sung Chun,Maxim Imakaev,Daniel Hui,Nikolaos A Patsopoulos,Benjamin M Neale,Sekar Kathiresan,Nathan O Stitziel,Shamil R Sunyaev

    In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait’s heritability. The highly polygenic nature of quantitative traits and most common phenotypes

    更新日期:2020-07-02
  • Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-12
    Minhui Chen,Carlo Sidore,Masato Akiyama,Kazuyoshi Ishigaki,Yoichiro Kamatani,David Schlessinger,Francesco Cucca,Yukinori Okada,Charleston W K Chiang

    Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population

    更新日期:2020-07-02
  • Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-06
    Alice B Popejoy,Kristy R Crooks,Stephanie M Fullerton,Lucia A Hindorff,Gillian W Hooker,Barbara A Koenig,Natalie Pino,Erin M Ramos,Deborah I Ritter,Hannah Wand,Matt W Wright,Michael Yudell,James Y Zou,Sharon E Plon,Carlos D Bustamante,Kelly E Ormond,

    Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia

    更新日期:2020-07-02
  • Natural Selection Shapes Codon Usage in the Human Genome.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-08
    Ryan S Dhindsa,Brett R Copeland,Anthony M Mustoe,David B Goldstein

    Synonymous codon usage has been identified as a determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, whether natural selection shapes human codon content to optimize translation efficiency is unclear. Furthermore, aside from those that affect splicing, synonymous mutations are typically ignored as potential contributors to disease. Using genetic

    更新日期:2020-07-02
  • Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-25
    Kyung-Hee Kim; Eun Pyo Hong; Jun Wan Shin; Michael J. Chao; Jacob Loupe; Tammy Gillis; Jayalakshmi S. Mysore; Peter Holmans; Lesley Jones; Michael Orth; Darren G. Monckton; Jeffrey D. Long; Seung Kwak; Ramee Lee; James F. Gusella; Marcy E. MacDonald; Jong-Min Lee

    A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find

    更新日期:2020-07-02
  • High-Throughput Reclassification of SCN5A Variants.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-12
    Andrew M Glazer,Yuko Wada,Bian Li,Ayesha Muhammad,Olivia R Kalash,Matthew J O'Neill,Tiffany Shields,Lynn Hall,Laura Short,Marcia A Blair,Brett M Kroncke,John A Capra,Dan M Roden

    Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence

    更新日期:2020-07-02
  • Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-22
    Madison R. Bishop; Kimberly K. Diaz Perez; Miranda Sun; Samantha Ho; Pankaj Chopra; Nandita Mukhopadhyay; Jacqueline B. Hetmanski; Margaret A. Taub; Lina M. Moreno-Uribe; Luz Consuelo Valencia-Ramirez; Claudia P. Restrepo Muñeton; George Wehby; Jacqueline T. Hecht; Frederic Deleyiannis; Seth M. Weinberg; Yah Huei Wu-Chou; Philip K. Chen; Harrison Brand; Elizabeth J. Leslie

    Although de novo mutations (DNMs) are known to increase an individual’s risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual’s OFC

    更新日期:2020-07-02
  • Population-Specific Recombination Maps from Segments of Identity by Descent.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-12
    Ying Zhou,Brian L Browning,Sharon R Browning

    Recombination rates vary significantly across the genome, and estimates of recombination rates are needed for downstream analyses such as haplotype phasing and genotype imputation. Existing methods for recombination rate estimation are limited by insufficient amounts of informative genetic data or by high computational cost. We present a method and software, called IBDrecomb, for using segments of

    更新日期:2020-07-02
  • A Genetic History of the Near East from an aDNA Time Course Sampling Eight Points in the Past 4,000 Years.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Marc Haber,Joyce Nassar,Mohamed A Almarri,Tina Saupe,Lehti Saag,Samuel J Griffith,Claude Doumet-Serhal,Julien Chanteau,Muntaha Saghieh-Beydoun,Yali Xue,Christiana L Scheib,Chris Tyler-Smith

    The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean

    更新日期:2020-07-02
  • Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-08
    Lynn M Boyden,Jing Zhou,Ronghua Hu,Theodore Zaki,Erin Loring,Jared Scott,Heiko Traupe,Amy S Paller,Richard P Lifton,Keith A Choate

    The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive

    更新日期:2020-07-02
  • De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-17
    Lisenka E L M Vissers,Sreehari Kalvakuri,Elke de Boer,Sinje Geuer,Machteld Oud,Inge van Outersterp,Michael Kwint,Melde Witmond,Simone Kersten,Daniel L Polla,Dilys Weijers,Amber Begtrup,Kirsty McWalter,Anna Ruiz,Elisabeth Gabau,Jenny E V Morton,Christopher Griffith,Karin Weiss,Candace Gamble,James Bartley,Hilary J Vernon,Kendra Brunet,Claudia Ruivenkamp,Sarina G Kant,Paul Kruszka,Austin Larson,Alexandra

    CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral

    更新日期:2020-07-02
  • Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-02
    Chunyu Liu; Haruhiko Miyata; Yang Gao; Yanwei Sha; Shuyan Tang; Zoulan Xu; Marjorie Whitfield; Catherine Patrat; Huan Wu; Emmanuel Dulioust; Shixiong Tian; Keisuke Shimada; Jiangshan Cong; Taichi Noda; Hang Li; Akane Morohoshi; Caroline Cazin; Zine-Eddine Kherraf; Masahito Ikawa

    Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing

    更新日期:2020-07-02
  • A Fast and Accurate Method for Genome-Wide Time-to-Event Data Analysis and Its Application to UK Biobank
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-25
    Wenjian Bi; Lars G. Fritsche; Bhramar Mukherjee; Sehee Kim; Seunggeun Lee

    With increasing biobanking efforts connecting electronic health records and national registries to germline genetics, the time-to-event data analysis has attracted increasing attention in the genetics studies of human diseases. In time-to-event data analysis, the Cox proportional hazards (PH) regression model is one of the most used approaches. However, existing methods and tools are not scalable when

    更新日期:2020-06-25
  • Regional Variation of Splicing QTLs in Human Brain
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-25
    Yida Zhang; Harry Taegyun Yang; Kathryn Kadash-Edmondson; Yang Pan; Zhicheng Pan; Beverly L. Davidson; Yi Xing

    A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq)

    更新日期:2020-06-25
  • Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-22
    Marcus Tuke; Jessica Tyrrell; Katherine S. Ruth; Robin N. Beaumont; Andrew R. Wood; Anna Murray; Timothy M. Frayling; Michael N. Weedon; Caroline F. Wright

    Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed

    更新日期:2020-06-22
  • 更新日期:2020-06-04
  • Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Juan R González,Carlos Ruiz-Arenas,Alejandro Cáceres,Ignasi Morán,Marcos López-Sánchez,Lorena Alonso,Ignacio Tolosana,Marta Guindo-Martínez,Josep M Mercader,Tonu Esko,David Torrents,Josefa González,Luis A Pérez-Jurado

    The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed

    更新日期:2020-05-28
  • Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Uirá Souto Melo,Robert Schöpflin,Rocio Acuna-Hidalgo,Martin Atta Mensah,Björn Fischer-Zirnsak,Manuel Holtgrewe,Marius-Konstantin Klever,Seval Türkmen,Verena Heinrich,Ilina Datkhaeva Pluym,Eunice Matoso,Sérgio Bernardo de Sousa,Pedro Louro,Wiebke Hülsemann,Monika Cohen,Andreas Dufke,Anna Latos-Bieleńska,Martin Vingron,Vera Kalscheuer,Fabiola Quintero-Rivera,Malte Spielmann,Stefan Mundlos

    Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression

    更新日期:2020-05-28
  • Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Sabrina Mechaussier,Basamat Almoallem,Christina Zeitz,Kristof Van Schil,Laila Jeddawi,Jo Van Dorpe,Alfredo Dueñas Rey,Christel Condroyer,Olivier Pelle,Michel Polak,Nathalie Boddaert,Nadia Bahi-Buisson,Mara Cavallin,Jean-Louis Bacquet,Alexandra Mouallem-Bézière,Olivia Zambrowski,José Alain Sahel,Isabelle Audo,Josseline Kaplan,Jean-Michel Rozet,Elfride De Baere,Isabelle Perrault

    Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD

    更新日期:2020-05-28
  • Localizing Components of Shared Transethnic Genetic Architecture of Complex Traits from GWAS Summary Data.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-21
    Huwenbo Shi,Kathryn S Burch,Ruth Johnson,Malika K Freund,Gleb Kichaev,Nicholas Mancuso,Astrid M Manuel,Natalie Dong,Bogdan Pasaniuc

    Despite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared

    更新日期:2020-05-21
  • An Integrated Deep-Mutational-Scanning Approach Provides Clinical Insights on PTEN Genotype-Phenotype Relationships.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-21
    Taylor L Mighell,Stetson Thacker,Eric Fombonne,Charis Eng,Brian J O'Roak

    Germline variation in PTEN results in variable clinical presentations, including benign and malignant neoplasia and neurodevelopmental disorders. Despite decades of research, it remains unclear how the PTEN genotype is related to clinical outcomes. In this study, we combined two recent deep mutational scanning (DMS) datasets probing the effects of single amino acid variation on enzyme activity and

    更新日期:2020-05-21
  • De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-21
    Dara Tolchin,Jessica P Yeager,Priya Prasad,Naghmeh Dorrani,Alvaro Serrano Russi,Julian A Martinez-Agosto,Abdul Haseeb,Marco Angelozzi,G W E Santen,Claudia Ruivenkamp,Saadet Mercimek-Andrews,Christel Depienne,Alma Kuechler,Barbara Mikat,Hermann-Josef Ludecke,Frederic Bilan,Gwenael Le Guyader,Brigitte Gilbert-Dussardier,Boris Keren,Solveig Heide,Damien Haye,Hilde Van Esch,Liesbeth Keldermans,Damara Ortiz

    SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as

    更新日期:2020-05-21
  • Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and Complex Disease Traits.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-21
    Lindsey K Stolze,Austin C Conklin,Michael B Whalen,Maykel López Rodríguez,Kadri Õunap,Ilakya Selvarajan,Anu Toropainen,Tiit Örd,Jin Li,Anna Eshghi,Alice E Solomon,Yun Fang,Minna U Kaikkonen,Casey E Romanoski

    The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes

    更新日期:2020-05-21
  • Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-14
    Jianwen Deng,Jiaxi Yu,Pidong Li,Xinghua Luan,Li Cao,Juan Zhao,Meng Yu,Wei Zhang,He Lv,Zhiying Xie,LingChao Meng,Yiming Zheng,Yawen Zhao,Qiang Gang,Qingqing Wang,Jing Liu,Min Zhu,Xueyu Guo,Yanan Su,Yu Liang,Fan Liang,Tomohiro Hayashi,Meiko Hashimoto Maeda,Tatsuro Sato,Shigehisa Ura,Yasushi Oya,Masashi Ogasawara,Aritoshi Iida,Ichizo Nishino,Chang Zhou,Chuanzhu Yan,Yun Yuan,Daojun Hong,Zhaoxia Wang

    Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative

    更新日期:2020-05-14
  • Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-14
    Thuy-Linh Le,Yunia Sribudiani,Xiaomin Dong,Céline Huber,Chelsea Kois,Geneviève Baujat,Christopher T Gordon,Valerie Mayne,Louise Galmiche,Valérie Serre,Nicolas Goudin,Mohammed Zarhrate,Christine Bole-Feysot,Cécile Masson,Patrick Nitschké,Frans W Verheijen,Lynn Pais,Anna Pelet,Simon Sadedin,John A Pugh,Natasha Shur,Susan M White,Salima El Chehadeh,John Christodoulou,Valérie Cormier-Daire,R M W Hofstra

    The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception

    更新日期:2020-05-14
  • Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-14
    Nelson K Kibinge,Caroline L Relton,Tom R Gaunt,Tom G Richardson

    Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression

    更新日期:2020-05-14
  • Mantis-ml: Disease-Agnostic Gene Prioritization from High-Throughput Genomic Screens by Stochastic Semi-supervised Learning.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-07
    Dimitrios Vitsios,Slavé Petrovski

    Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses. However, gene signals are often insufficiently powered to reach experiment-wide significance, triggering a process of laborious triaging of genomic-association-study results. We introduce mantis-ml, a multi-dimensional, multi-step machine-learning framework that allows objective assessment of

    更新日期:2020-05-07
  • Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-07
    Ozan Dikilitas,Daniel J Schaid,Matthew L Kosel,Robert J Carroll,Christopher G Chute,Joshua A Denny,Alex Fedotov,QiPing Feng,Hakon Hakonarson,Gail P Jarvik,Ming Ta Michael Lee,Jennifer A Pacheco,Robb Rowley,Patrick M Sleiman,C Michael Stein,Amy C Sturm,Wei-Qi Wei,Georgia L Wiesner,Marc S Williams,Yanfei Zhang,Teri A Manolio,Iftikhar J Kullo

    Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included

    更新日期:2020-05-07
  • Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-07
    Ridge Dershem,Caroline M Gorvin,Raghu P R Metpally,Sarathbabu Krishnamurthy,Diane T Smelser,Fadil M Hannan,David J Carey,Rajesh V Thakker,Gerda E Breitwieser,

    The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the

    更新日期:2020-05-07
  • Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-07
    Julia Ramírez,Stefan van Duijvenboden,William J Young,Michele Orini,Pier D Lambiase,Patricia B Munroe,Andrew Tinker

    Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding

    更新日期:2020-05-07
  • Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-07
    Benjamin Cogné,Xenia Latypova,Lokuliyanage Dona Samudita Senaratne,Ludovic Martin,Daniel C Koboldt,Georgios Kellaris,Lorraine Fievet,Guylène Le Meur,Dominique Caldari,Dominique Debray,Mathilde Nizon,Eirik Frengen,Sara J Bowne,,Elizabeth L Cadena,Stephen P Daiger,Kinga M Bujakowska,Eric A Pierce,Michael Gorin,Nicholas Katsanis,Stéphane Bézieau,Simon M Petersen-Jones,Laurence M Occelli,Leslie A Lyons

    Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband

    更新日期:2020-05-07
  • Insufficient Evidence for "Autism-Specific" Genes.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-30
    Scott M Myers,Thomas D Challman,Raphael Bernier,Thomas Bourgeron,Wendy K Chung,John N Constantino,Evan E Eichler,Sebastien Jacquemont,David T Miller,Kevin J Mitchell,Huda Y Zoghbi,Christa Lese Martin,David H Ledbetter

    Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes

    更新日期:2020-04-30
  • Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-30
    Andrew P Badrock,Carolina Uggenti,Ludivine Wacheul,Siobhan Crilly,Emma M Jenkinson,Gillian I Rice,Paul R Kasher,Denis L J Lafontaine,Yanick J Crow,Raymond T O'Keefe

    How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which

    更新日期:2020-04-30
  • Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-23
    J Nicholas Cochran,Ethan G Geier,Luke W Bonham,J Scott Newberry,Michelle D Amaral,Michelle L Thompson,Brittany N Lasseigne,Anna M Karydas,Erik D Roberson,Gregory M Cooper,Gil D Rabinovici,Bruce L Miller,Richard M Myers,Jennifer S Yokoyama,

    We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction

    更新日期:2020-04-23
  • De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-23
    Hyung-Lok Chung,Xiao Mao,Hua Wang,Ye-Jin Park,Paul C Marcogliese,Jill A Rosenfeld,Lindsay C Burrage,Pengfei Liu,David R Murdock,Shinya Yamamoto,Michael F Wangler,,Hsiao-Tuan Chao,Hongyu Long,Li Feng,Carlos A Bacino,Hugo J Bellen,Bo Xiao

    We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities

    更新日期:2020-04-23
  • Accurate and Scalable Construction of Polygenic Scores in Large Biobank Data Sets.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-23
    Sheng Yang,Xiang Zhou

    Accurate construction of polygenic scores (PGS) can enable early diagnosis of diseases and facilitate the development of personalized medicine. Accurate PGS construction requires prediction models that are both adaptive to different genetic architectures and scalable to biobank scale datasets with millions of individuals and tens of millions of genetic variants. Here, we develop such a method called

    更新日期:2020-04-23
  • Reproductive Choice and Research
    Am. J. Hum. Genet. (IF 10.502) 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:2020-04-20
  • A Fast and Simple Method for Detecting Identity-by-Descent Segments in Large-Scale Data.
    Am. J. Hum. Genet. (IF 10.502) 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:2020-04-20
  • 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 10.502) 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,Ganka Douglas,Yue Cindy Si,Jamel Chelly,Zohra Shad,Elisabeth Kaplan,Richard Dineen,Christelle Golzio,Nicolas

    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:2020-04-20
  • Rapid, Phase-free Detection of Long Identity-by-Descent Segments Enables Effective Relationship Classification.
    Am. J. Hum. Genet. (IF 10.502) 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

    Identity-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 of

    更新日期:2020-04-20
  • Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.
    Am. J. Hum. Genet. (IF 10.502) 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,John Christodoulou,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:2020-04-20
  • Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.
    Am. J. Hum. Genet. (IF 10.502) 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,Ange-Line Bruel,Christel Thauvin-Robinet,Athina Ververi,Catherine DeVile,Alison Male,Stephanie Efthymiou,Reza Maroofian

    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:2020-04-20
  • Genetic Architecture of Gene Expression in European and African Americans: An eQTL Mapping Study in GENOA.
    Am. J. Hum. Genet. (IF 10.502) 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:2020-04-20
  • Co-localization between Sequence Constraint and Epigenomic Information Improves Interpretation of Whole-Genome Sequencing Data.
    Am. J. Hum. Genet. (IF 10.502) 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:2020-04-20
  • Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos.
    Am. J. Hum. Genet. (IF 10.502) 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:2020-04-20
  • Genotyping Array Design and Data Quality Control in the Million Veteran Program.
    Am. J. Hum. Genet. (IF 10.502) 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,Mary Brophy,Jennifer Moser,Sumitra Muralidhar,Grant D Huang,Ronald Przygodzki,John Concato,John M Gaziano,Joel Gelernter,Christopher J O'Donnell

    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:2020-04-20
  • De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy.
    Am. J. Hum. Genet. (IF 10.502) 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,Hirotomo Saitsu,Satomi Mitsuhashi,Takeshi Mizuguchi,Atsushi Takata,Noriko Miyake,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:2020-04-20
  • 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 10.502) 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:2020-04-20
  • De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
    Am. J. Hum. Genet. (IF 10.502) 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,Luigina Spaccini,Maria Iascone,Casie A Genetti,Mary K Koenig,Madeline Graf,Alyssa Tran,Mercedes Alejandro,,Brendan H Lee,Isabelle

    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:2020-04-20
  • Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-16
    Daniel I Chasman,Franco Giulianini,Olga V Demler,Miriam S Udler

    Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation

    更新日期:2020-04-16
  • Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-09
    Christopher DeBoever,Yosuke Tanigawa,Matthew Aguirre,Greg McInnes,Adam Lavertu,Manuel A Rivas

    Population-scale biobanks that combine genetic data and high-dimensional phenotyping for a large number of participants provide an exciting opportunity to perform genome-wide association studies (GWAS) to identify genetic variants associated with diverse quantitative traits and diseases. A major challenge for GWAS in population biobanks is ascertaining disease cases from heterogeneous data sources

    更新日期:2020-04-09
  • Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-04-09
    Alison M Muir,Jennifer L Cohen,Sarah E Sheppard,Pavithran Guttipatti,Tsz Y Lo,Natalie Weed,Dan Doherty,Danielle DeMarzo,Christina R Fagerberg,Lars Kjærsgaard,Martin J Larsen,Patrick Rump,Katharina Löhner,Yoel Hirsch,David A Zeevi,Elaine H Zackai,Elizabeth Bhoj,Yuanquan Song,Heather C Mefford

    Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes

    更新日期:2020-04-09
  • DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.
    Am. J. Hum. Genet. (IF 10.502) 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,Frances Flinter,Vivienne McConnell,Tom Cushing,Lynne M Bird,Miranda Splitt,Bronwyn Kerr,Stephen W Scherer,Jerry Machado,Eri Imagawa

    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:2020-04-02
  • Population Histories of the United States Revealed through Fine-Scale Migration and Haplotype Analysis.
    Am. J. Hum. Genet. (IF 10.502) 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 10.502) 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,,Alan Pittman,João Ricardo Mendes de Oliveira,Maria de Grandis,Angela Richard-Loendt,Francesca Launchbury,Juri Althonayan,Gavin

    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 10.502) Pub Date : 2020-02-27
    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
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