11,688 results match your criteria American journal of human genetics[Journal]


Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and Complex Disease Traits.

Am J Hum Genet 2020 May 16. Epub 2020 May 16.

Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ 85721, USA. Electronic address:

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 in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expression Project (GTEx) in human tissues, showing that novel biological relationships unique to endothelial cells (ECs) are enriched in this dataset. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.008DOI Listing

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 May 19. Epub 2020 May 19.

Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale, 31000 Toulouse, France. Electronic address:

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 SOXopathies. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.015DOI Listing

An Integrated Deep-Mutational-Scanning Approach Provides Clinical Insights on PTEN Genotype-Phenotype Relationships.

Am J Hum Genet 2020 May 21. Epub 2020 May 21.

Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:

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 steady-state cellular abundance with a large, well-curated clinical cohort of PTEN-variant carriers. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.014DOI Listing

Localizing Components of Shared Transethnic Genetic Architecture of Complex Traits from GWAS Summary Data.

Am J Hum Genet 2020 May 13. Epub 2020 May 13.

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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 causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.012DOI Listing

Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data.

Am J Hum Genet 2020 May 10. Epub 2020 May 10.

Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom. Electronic address:

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, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.007DOI Listing

Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.

Am J Hum Genet 2020 May 12. Epub 2020 May 12.

Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France. Electronic address:

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 system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.010DOI Listing

Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy.

Am J Hum Genet 2020 May 10. Epub 2020 May 10.

Department of Neurology, Peking University First Hospital, Beijing 100034, China. Electronic address:

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 autosomal-dominant or autosomal-recessive pattern. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.011DOI Listing
May 2020
10.931 Impact Factor

Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.

Am J Hum Genet 2020 Apr 29. Epub 2020 Apr 29.

Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.009DOI Listing

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.

Am J Hum Genet 2020 Apr 29. Epub 2020 Apr 29.

Regeneron Genetics Center, Tarrytown, NY 10591, USA.

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 DiscovEHR cohort derived from a single US healthcare system. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.006DOI Listing

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Am J Hum Genet 2020 Apr 28. Epub 2020 Apr 28.

CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.005DOI Listing

Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups.

Am J Hum Genet 2020 May;106(5):707-716

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212267PMC

Mantis-ml: Disease-Agnostic Gene Prioritization from High-Throughput Genomic Screens by Stochastic Semi-supervised Learning.

Am J Hum Genet 2020 May;106(5):659-678

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, CB2 0RE Cambridge, UK. Electronic address:

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 the biological relevance of genes to disease studies. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212270PMC

Insufficient Evidence for "Autism-Specific" Genes.

Am J Hum Genet 2020 May 30;106(5):587-595. Epub 2020 Apr 30.

Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, USA. Electronic address:

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, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212289PMC
May 2020
10.931 Impact Factor

Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts.

Am J Hum Genet 2020 May 30;106(5):694-706. Epub 2020 Apr 30.

Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Electronic address:

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 monitors ribosome biogenesis. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212298PMC

Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases.

Am J Hum Genet 2020 May 23;106(5):632-645. Epub 2020 Apr 23.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, United States. Electronic address:

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 of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212268PMC

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.

Am J Hum Genet 2020 May 23;106(5):717-725. Epub 2020 Apr 23.

Neurology Department, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address:

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 in CDK19 are not known to be associated with a human disorder. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212481PMC
May 2020
10.931 Impact Factor

Accurate and Scalable Construction of Polygenic Scores in Large Biobank Data Sets.

Am J Hum Genet 2020 May 23;106(5):679-693. Epub 2020 Apr 23.

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

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 Deterministic Bayesian Sparse Linear Mixed Model (DBSLMM). Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212266PMC

Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD.

Am J Hum Genet 2020 May 16;106(5):646-658. Epub 2020 Apr 16.

Harvard Medical School, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA.

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 or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212269PMC

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.

Am J Hum Genet 2020 May 9;106(5):623-631. Epub 2020 Apr 9.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA. Electronic address:

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 and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212259PMC

Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases.

Am J Hum Genet 2020 May 9;106(5):611-622. Epub 2020 Apr 9.

Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. Electronic address:

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 such as hospital records, digital questionnaire responses, or interviews. In this study, we use genetic parameters, including genetic correlation, to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of disease implicate similar disease genetics across a range of effect sizes. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212271PMC

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Am J Hum Genet 2020 May 2;106(5):596-610. Epub 2020 Apr 2.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

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 DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212265PMC
May 2020
10.931 Impact Factor

Genotyping Array Design and Data Quality Control in the Million Veteran Program.

Am J Hum Genet 2020 04;106(4):535-548

VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Brigham and Women's Hospital and Harvard School of Medicine, Boston, MA 02115, USA. Electronic address:

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 medicine. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118558PMC

Co-localization between Sequence Constraint and Epigenomic Information Improves Interpretation of Whole-Genome Sequencing Data.

Am J Hum Genet 2020 04;106(4):513-524

Department of Biostatistics, Columbia University, New York, NY 10032, USA. Electronic address:

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 score is particularly well suited for the identification of rare regulatory variants. For 127 tissues and cell types in the ENCODE/Roadmap Epigenomics Project, we provide catalogs of putative tissue- or cell-type-specific regulatory regions under sequence constraint. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118583PMC

Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos.

Am J Hum Genet 2020 04 26;106(4):525-534. Epub 2020 Mar 26.

Igenomix Italy, 36063, Marostica, Italy; DAHFMO, Unit of Histology and Medical Embryology, Sapienza, University of Rome, 00161, Roma, Italy; Igenomix Foundation, 46980, Valencia, Spain. Electronic address:

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 and the diagnostic predictive value of segmental aneuploidy detection in TE biopsies toward the ICM's chromosomal constitution. Contrary to the prevalent meiotic origin of whole-chromosome aneuploidies, we show that sub-chromosomal abnormalities in human blastocysts arise from mitotic errors in around 70% of cases. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118577PMC
April 2020
10.931 Impact Factor

Genetic Architecture of Gene Expression in European and African Americans: An eQTL Mapping Study in GENOA.

Am J Hum Genet 2020 04 26;106(4):496-512. Epub 2020 Mar 26.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

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 with African ancestry and hinder the comparable analysis for understanding how gene regulation is shaped through evolution. We fill this critical knowledge gap by performing a large-scale in-depth eQTL mapping study on 1,032 African Americans (AA) and 801 European Americans (EA) in the GENOA cohort. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118581PMC

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

Am J Hum Genet 2020 04 26;106(4):467-483. Epub 2020 Mar 26.

Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118584PMC

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.

Am J Hum Genet 2020 04 26;106(4):484-495. Epub 2020 Mar 26.

CHU-Sainte Justine Research Center, University of Montreal, Montreal, QC, Canada, H3T1C5; Department of Pediatrics, University of Montreal, Montreal, QC, Canada, H3T1C5. Electronic address:

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 different bi-allelic PIGK variants. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118585PMC
April 2020
10.931 Impact Factor

Rapid, Phase-free Detection of Long Identity-by-Descent Segments Enables Effective Relationship Classification.

Am J Hum Genet 2020 04 19;106(4):453-466. Epub 2020 Mar 19.

Department of Computational Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address:

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 allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118564PMC
April 2020
10.931 Impact Factor

Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification.

Am J Hum Genet 2020 04 19;106(4):559-569. Epub 2020 Mar 19.

Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia; Victorian Clinical Genetics Services, Parkville, Victoria 3052, Australia. Electronic address:

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 had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118692PMC

De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.

Am J Hum Genet 2020 04 19;106(4):570-583. Epub 2020 Mar 19.

Department of Pediatrics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Program in Development, Disease Models, and Therapeutics, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX 77030, USA. Electronic address:

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 variants in EIF2AK1 and EIF2AK2 have not been reported. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118694PMC

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 2020 04 19;106(4):438-452. Epub 2020 Mar 19.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France. Electronic address:

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 (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118572PMC
April 2020
10.931 Impact Factor

A Fast and Simple Method for Detecting Identity-by-Descent Segments in Large-Scale Data.

Am J Hum Genet 2020 04 12;106(4):426-437. Epub 2020 Mar 12.

Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118582PMC

De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy.

Am J Hum Genet 2020 04 12;106(4):549-558. Epub 2020 Mar 12.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

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]. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118575PMC

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Am J Hum Genet 2020 03;106(3):412-421

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK; The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory and Clinical Service, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058839PMC

Population Histories of the United States Revealed through Fine-Scale Migration and Haplotype Analysis.

Am J Hum Genet 2020 03;106(3):371-388

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

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 Project. We identify migration routes and barriers that reflect historical demographic events. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058830PMC

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Authors:
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 Beekman Alexandra I Blakemore Federico Canzian Stephen E Hamby Jouke-Jan Hottenga Peter D Jones Pekka Jousilahti Reedik Mägi Sarah E Medland Grant W Montgomery Dale R Nyholt Markus Perola Kirsi H Pietiläinen Veikko Salomaa Elina Sillanpää H Eka Suchiman Diana van Heemst Gonneke Willemsen Antonio Agudo Heiner Boeing Dorret I Boomsma Maria-Dolores Chirlaque Guy Fagherazzi Pietro Ferrari Paul Franks Christian Gieger Johan Gunnar Eriksson Marc Gunter Sara Hägg Iiris Hovatta Liher Imaz Jaakko Kaprio Rudolf Kaaks Timothy Key Vittorio Krogh Nicholas G Martin Olle Melander Andres Metspalu Concha Moreno N Charlotte Onland-Moret Peter Nilsson Ken K Ong Kim Overvad Domenico Palli Salvatore Panico Nancy L Pedersen Brenda W J H Penninx J Ramón Quirós Marjo Riitta Jarvelin Miguel Rodríguez-Barranco Robert A Scott Gianluca Severi P Eline Slagboom Tim D Spector Anne Tjonneland Antonia Trichopoulou Rosario Tumino André G Uitterlinden Yvonne T van der Schouw Cornelia M van Duijn Elisabete Weiderpass Eros Lazzerini Denchi Giuseppe Matullo Adam S Butterworth John Danesh Nilesh J Samani Nicholas J Wareham Christopher P Nelson Claudia Langenberg Veryan Codd

Am J Hum Genet 2020 03 27;106(3):389-404. Epub 2020 Feb 27.

Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826PMC
March 2020
10.931 Impact Factor

De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):405-411. Epub 2020 Feb 27.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address:

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. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058825PMC

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):338-355. Epub 2020 Feb 27.

Wessex Clinical Genetics, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 5YA, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK. Electronic address:

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 the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058823PMC
March 2020
10.931 Impact Factor

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):356-370. Epub 2020 Feb 27.

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A3K7, Canada. Electronic address:

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 of ambiguous genetic test results. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058829PMC
March 2020
10.931 Impact Factor

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways.

Am J Hum Genet 2020 03 20;106(3):315-326. Epub 2020 Feb 20.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Electronic address:

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 (FEV) 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 two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058834PMC

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

Am J Hum Genet 2020 03 13;106(3):327-337. Epub 2020 Feb 13.

Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Medicine, McGill University Montreal, QC H3G 1Y6, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada; Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK. Electronic address:

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 imputation quality score > 0. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058824PMC

Influence of Genetic Ancestry on Human Serum Proteome.

Am J Hum Genet 2020 03 13;106(3):303-314. Epub 2020 Feb 13.

Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, 1280 Main Street West, Hamilton ON L8S 4K1, Canada; Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton ON L8S 4K1, Canada; Department of Biochemistry, McMaster University, 1280 Main Street West, Hamilton ON L8S 4K1, Canada. Electronic address:

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 the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058828PMC
March 2020
10.931 Impact Factor

Enhancer Domains Predict Gene Pathogenicity and Inform Gene Discovery in Complex Disease.

Am J Hum Genet 2020 02;106(2):215-233

Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 701 West 168th Street, New York, New York 10032, USA; Department of Genetics and Development, Columbia University Medical Center, Hammer Health Sciences, 701 West 168th Street, New York, New York 10032, USA. Electronic address:

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 non-coding mutations. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010980PMC
February 2020

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

Am J Hum Genet 2020 02;106(2):143-152

Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address:

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 this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010971PMC
February 2020
10.931 Impact Factor

Allele-Specific QTL Fine Mapping with PLASMA.

Am J Hum Genet 2020 02 30;106(2):170-187. Epub 2020 Jan 30.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Brigham & Women's Hospital, Division of Genetics, Boston, MA 02215, USA. Electronic address:

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 technical/environmental noise. However, existing methods for estimating causal variant probabilities (i. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011109PMC
February 2020

The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB.

Am J Hum Genet 2020 02 30;106(2):202-214. Epub 2020 Jan 30.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010979PMC
February 2020

Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.

Am J Hum Genet 2020 02 30;106(2):264-271. Epub 2020 Jan 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

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 sets (175 cases, 1,059 controls). Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010969PMC
February 2020
10.931 Impact Factor

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Am J Hum Genet 2020 02 30;106(2):246-255. Epub 2020 Jan 30.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany. Electronic address:

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 activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010976PMC
February 2020
10.931 Impact Factor

Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease.

Am J Hum Genet 2020 02 30;106(2):256-263. Epub 2020 Jan 30.

Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. Electronic address:

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 of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. Read More

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http://dx.doi.org/10.1016/j.ajhg.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010975PMC
February 2020