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    Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.
    Am J Hum Genet 2018 May 17. Epub 2018 May 17.
    Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Michigan Institute for Data Science, University of Michigan, Ann Arbor, MI 48109, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:
    Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. Read More

    A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies.
    Am J Hum Genet 2018 Apr 30. Epub 2018 Apr 30.
    Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. Electronic address:
    Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWASs) strongly suggests that variants important to human diseases often lie in non-coding regions. Read More

    Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    Am J Hum Genet 2018 May 10. Epub 2018 May 10.
    Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel. Electronic address:
    Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Read More

    Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory.
    Am J Hum Genet 2018 May 3. Epub 2018 May 3.
    Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:
    Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Read More

    Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood.
    Am J Hum Genet 2018 Apr 26. Epub 2018 Apr 26.
    Centre for Population Health Research, School of Health Sciences and Sansom Institute of Health Research, University of South Australia, Adelaide, SA 5000, Australia; School of Environmental and Rural Science, University of New England, Armidale, NSW 2351, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:
    Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e. Read More

    Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms.
    Am J Hum Genet 2018 May;102(5):973-984
    Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address:
    Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Read More

    C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.
    Am J Hum Genet 2018 May;102(5):956-972
    Genetics and Genomic Medicine Programme, University College London, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. Electronic address:
    Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder characterized by destructive respiratory disease and laterality abnormalities due to randomized left-right body asymmetry. PCD is mostly caused by mutations affecting the core axoneme structure of motile cilia that is essential for movement. Genes that cause PCD when mutated include a group that encode proteins essential for the assembly of the ciliary dynein motors and the active transport process that delivers them from their cytoplasmic assembly site into the axoneme. Read More

    FUN-LDA: A Latent Dirichlet Allocation Model for Predicting Tissue-Specific Functional Effects of Noncoding Variation: Methods and Applications.
    Am J Hum Genet 2018 May;102(5):920-942
    Department of Biostatistics, Columbia University, New York, NY 10032, USA. Electronic address:
    We describe a method based on a latent Dirichlet allocation model for predicting functional effects of noncoding genetic variants in a cell-type- and/or tissue-specific way (FUN-LDA). Using this unsupervised approach, we predict tissue-specific functional effects for every position in the human genome in 127 different tissues and cell types. We demonstrate the usefulness of our predictions by using several validation experiments. Read More

    A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics.
    Am J Hum Genet 2018 May;102(5):904-919
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address:
    Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. Read More

    A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies.
    Am J Hum Genet 2018 May;102(5):890-903
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
    Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. Read More

    Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes.
    Am J Hum Genet 2018 May;102(5):874-889
    Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. Electronic address:
    Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in line with expectations given the underlying population and ascertainment approach. Read More

    Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.
    Am J Hum Genet 2018 May;102(5):858-873
    Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
    The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. Read More

    The Post-GWAS Era: From Association to Function.
    Am J Hum Genet 2018 May;102(5):717-730
    Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
    During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. Read More

    Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms.
    Am J Hum Genet 2018 May 26;102(5):816-831. Epub 2018 Apr 26.
    Kidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address:
    Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. Read More

    Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.
    Am J Hum Genet 2018 May 26;102(5):731-743. Epub 2018 Apr 26.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; USDA/ARS/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:
    Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. Read More

    Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.
    Am J Hum Genet 2018 May 26;102(5):832-844. Epub 2018 Apr 26.
    Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:
    Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. Read More

    A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.
    Am J Hum Genet 2018 May 26;102(5):943-955. Epub 2018 Apr 26.
    Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:
    Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Read More

    Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland.
    Am J Hum Genet 2018 May 26;102(5):760-775. Epub 2018 Apr 26.
    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; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland. Electronic address:
    Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. Read More

    Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese.
    Am J Hum Genet 2018 May 26;102(5):794-805. Epub 2018 Apr 26.
    Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, Yunnan 650223, China. Electronic address:
    Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. Read More

    The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance.
    Am J Hum Genet 2018 May 26;102(5):845-857. Epub 2018 Apr 26.
    Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address:
    Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Read More

    An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation.
    Am J Hum Genet 2018 May 26;102(5):776-793. Epub 2018 Apr 26.
    Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China. Electronic address:
    Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36. Read More

    Patterns of Genetic Coding Variation in a Native American Population before and after European Contact.
    Am J Hum Genet 2018 May 26;102(5):806-815. Epub 2018 Apr 26.
    Departments of Biology and Statistics, Pennsylvania State University, University Park, PA 16801, USA; Institute for CyberScience, Pennsylvania State University, University Park, PA 16801, USA. Electronic address:
    The effects of European colonization on the genomes of Native Americans may have produced excesses of potentially deleterious features, mainly due to the severe reductions in population size and corresponding losses of genetic diversity. This assumption, however, neither considers actual genomic patterns that existed before colonization nor does it adequately capture the effects of admixture. In this study, we analyze the whole-exome sequences of modern and ancient individuals from a Northwest Coast First Nation, with a demographic history similar to other indigenous populations from the Americas. Read More

    Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.
    Am J Hum Genet 2018 May 12;102(5):985-994. Epub 2018 Apr 12.
    Stanley Institute for Cognitive Genomics, 1Bungtown Road, Cold Spring Harbor Laboratory, NY 11724, USA. Electronic address:
    N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p. Read More

    Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.
    Am J Hum Genet 2018 May 12;102(5):744-759. Epub 2018 Apr 12.
    Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; l'institut du thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France. Electronic address:
    RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Read More

    A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.
    Am J Hum Genet 2018 May 12;102(5):995-1007. Epub 2018 Apr 12.
    Centre de Génétique Médicale, Centre de Référence "Déficiences Intellectuelles de causes rares," CHU de Dijon Bourgogne, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France. Electronic address:
    Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Read More

    LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.
    Am J Hum Genet 2018 Apr;102(4):706-712
    Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address:
    The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p. Read More

    A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression.
    Am J Hum Genet 2018 Apr;102(4):620-635
    Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Institute of Systems Genomics, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address:
    Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Read More

    Identification of Misclassified ClinVar Variants via Disease Population Prevalence.
    Am J Hum Genet 2018 Apr;102(4):609-619
    J. Craig Venter Institute, La Jolla, CA 92037, USA. Electronic address:
    There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. Read More

    L-GATOR: Genetic Association Testing for a Longitudinally Measured Quantitative Trait in Samples with Related Individuals.
    Am J Hum Genet 2018 Apr;102(4):574-591
    Department of Statistics, The University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. Electronic address:
    In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals. Read More

    PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses and Clinical Measures across 38,662 Individuals from Geisinger.
    Am J Hum Genet 2018 Apr 29;102(4):592-608. Epub 2018 Mar 29.
    Biomedical and Translational Informatics Institute, Geisinger Health System, Danville, PA 17822, USA. Electronic address:
    Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency > 0. Read More

    Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome.
    Am J Hum Genet 2018 Apr 29;102(4):696-705. Epub 2018 Mar 29.
    Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA; Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:
    AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. Read More

    Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse.
    Am J Hum Genet 2018 Apr;102(4):636-648
    Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000 Grenoble, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, 38000 Grenoble, France. Electronic address:
    The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Read More

    Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility.
    Am J Hum Genet 2018 Apr 29;102(4):649-657. Epub 2018 Mar 29.
    State Key Laboratory of Genetic Engineering and School of Life Sciences, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address:
    Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. Read More

    Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies.
    Am J Hum Genet 2018 Apr 22;102(4):685-695. Epub 2018 Mar 22.
    Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:
    Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Read More

    Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.
    Am J Hum Genet 2018 Apr 22;102(4):557-573. Epub 2018 Mar 22.
    Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel 24105, Germany; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:
    Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Read More

    Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.
    Am J Hum Genet 2018 Apr 22;102(4):676-684. Epub 2018 Mar 22.
    Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, QC H4A 3J1, Canada. Electronic address:
    Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. Read More

    Relationship between Deleterious Variation, Genomic Autozygosity, and Disease Risk: Insights from The 1000 Genomes Project.
    Am J Hum Genet 2018 Apr 15;102(4):658-675. Epub 2018 Mar 15.
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
    Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations-relatively untouched by purifying selection-being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome sequence data on 27 individuals. Read More

    Outcomes of Counseling after Education about Carrier Results: A Randomized Controlled Trial.
    Am J Hum Genet 2018 Apr 8;102(4):540-546. Epub 2018 Mar 8.
    Social and Behavioral Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address:
    In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. Read More

    Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity.
    Am J Hum Genet 2018 Apr 8;102(4):528-539. Epub 2018 Mar 8.
    UCL Institute of Ophthalmology, London ECIV 9EL, UK. Electronic address:
    Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. Read More

    Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase.
    Am J Hum Genet 2018 Apr 8;102(4):547-556. Epub 2018 Mar 8.
    Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD 20892, USA. Electronic address:
    Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p. Read More

    Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease.
    Am J Hum Genet 2018 Apr 8;102(4):517-527. Epub 2018 Mar 8.
    Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 EN Nijmegen, the Netherlands. Electronic address:
    Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. Read More

    Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.
    Am J Hum Genet 2018 Mar;102(3):505-514
    Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:
    Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na,K-ATPase, as a cause of autosomal-dominant CMT2. Read More

    Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4.
    Am J Hum Genet 2018 Mar;102(3):447-459
    UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK. Electronic address:
    In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Read More

    Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.
    Am J Hum Genet 2018 Mar;102(3):427-446
    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Comparative and Molecular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:
    Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. Read More

    2017 Curt Stern Award Introduction: Nico Katsanis.
    Am J Hum Genet 2018 Mar;102(3):354
    Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, 6500 GA, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands. Electronic address:

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