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    11216 results match your criteria American journal of human genetics[Journal]

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    Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans.
    Am J Hum Genet 2018 Jan 9. Epub 2018 Jan 9.
    Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. Electronic address:
    Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Read More

    Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.
    Am J Hum Genet 2018 Jan;102(1):88-102
    Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands. Electronic address:
    Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. Read More

    The Comoros Show the Earliest Austronesian Gene Flow into the Swahili Corridor.
    Am J Hum Genet 2018 Jan;102(1):58-68
    Evolutionary Medicine Group, Laboratoire d'Anthropologie Moléculaire et Imagerie de Synthèse UMR 5288 CNRS, Université Toulouse III, Université de Toulouse, Toulouse 31073, France. Electronic address:
    At the dawn of the second millennium, the expansion of the Indian Ocean trading network aligned with the emergence of an outward-oriented community along the East African coast to create a cosmopolitan cultural and trading zone known as the Swahili Corridor. On the basis of analyses of new genome-wide genotyping data and uniparental data in 276 individuals from coastal Kenya and the Comoros islands, along with large-scale genetic datasets from the Indian Ocean rim, we reconstruct historical population dynamics to show that the Swahili Corridor is largely an eastern Bantu genetic continuum. Limited gene flows from the Middle East can be seen in Swahili and Comorian populations at dates corresponding to historically documented contacts. Read More

    HIPAA's Individual Right of Access to Genomic Data: Reconciling Safety and Civil Rights.
    Am J Hum Genet 2018 Jan;102(1):5-10
    Law Center and Department of Electrical and Computer Engineering, University of Houston, Houston, TX 77204, USA. Electronic address:
    In 2014, the United States granted individuals a right of access to their own laboratory test results, including genomic data. Many observers feel that this right is in tension with regulatory and bioethical standards designed to protect the safety of people who undergo genomic testing. This commentary attributes this tension to growing pains within an expanding federal regulatory program for genetic and genomic testing. Read More

    Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation.
    Am J Hum Genet 2018 Jan;102(1):188-195
    Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:
    Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. Read More

    Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes.
    Am J Hum Genet 2018 Jan;102(1):156-174
    Department of Pathology and Laboratory Medicine, Western University, London, ON N6A5C1, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada. Electronic address:
    Pediatric developmental syndromes present with systemic, complex, and often overlapping clinical features that are not infrequently a consequence of Mendelian inheritance of mutations in genes involved in DNA methylation, establishment of histone modifications, and chromatin remodeling (the "epigenetic machinery"). The mechanistic cross-talk between histone modification and DNA methylation suggests that these syndromes might be expected to display specific DNA methylation signatures that are a reflection of those primary errors associated with chromatin dysregulation. Given the interrelated functions of these chromatin regulatory proteins, we sought to identify DNA methylation epi-signatures that could provide syndrome-specific biomarkers to complement standard clinical diagnostics. Read More

    A Comprehensive Workflow for Read Depth-Based Identification of Copy-Number Variation from Whole-Genome Sequence Data.
    Am J Hum Genet 2018 Jan;102(1):142-155
    The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada. Electronic address:
    A remaining hurdle to whole-genome sequencing (WGS) becoming a first-tier genetic test has been accurate detection of copy-number variations (CNVs). Here, we used several datasets to empirically develop a detailed workflow for identifying germline CNVs >1 kb from short-read WGS data using read depth-based algorithms. Our workflow is comprehensive in that it addresses all stages of the CNV-detection process, including DNA library preparation, sequencing, quality control, reference mapping, and computational CNV identification. Read More

    Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm.
    Am J Hum Genet 2018 Jan;102(1):133-141
    INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France; CHU Nantes, l'institut du thorax, 44093 Nantes, France. Electronic address:
    Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. Read More

    The Expanding Landscape of Alternative Splicing Variation in Human Populations.
    Am J Hum Genet 2018 Jan;102(1):11-26
    Department of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:
    Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed researchers to investigate alternative splicing at an unprecedented scale and resolution. Read More

    Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.
    Am J Hum Genet 2018 Jan 28;102(1):69-87. Epub 2017 Dec 28.
    Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address:
    Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p. Read More

    KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.
    Am J Hum Genet 2018 Jan 28;102(1):116-132. Epub 2017 Dec 28.
    Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address:
    Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Read More

    Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.
    Am J Hum Genet 2018 Jan 28;102(1):103-115. Epub 2017 Dec 28.
    Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:
    Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Read More

    WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
    Am J Hum Genet 2018 Jan 21;102(1):27-43. Epub 2017 Dec 21.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA. Electronic address:
    Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. Read More

    Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
    Am J Hum Genet 2018 Jan 21;102(1):175-187. Epub 2017 Dec 21.
    Manchester Centre for Genomic Medicine, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK. Electronic address:
    Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. Read More

    Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.
    Am J Hum Genet 2018 Jan 21;102(1):44-57. Epub 2017 Dec 21.
    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address:
    Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Read More

    Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.
    Am J Hum Genet 2017 Dec;101(6):965-976
    Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address:
    Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p. Read More

    A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance via GWAS Summary Statistics.
    Am J Hum Genet 2017 Dec;101(6):939-964
    Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06510, USA; VA Cooperative Studies Program Coordinating Center, West Haven, CT 06516, USA. Electronic address:
    Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits' genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Read More

    Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass Index Distribution.
    Am J Hum Genet 2017 Dec;101(6):925-938
    Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address:
    A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)-rs1421085 (FTO; p = 8. Read More

    ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder.
    Am J Hum Genet 2017 Dec;101(6):1021-1033
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, M13 9PL Manchester, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, M13 9WL Manchester, UK. Electronic address:
    ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. Read More

    De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities.
    Am J Hum Genet 2017 Dec;101(6):1013-1020
    Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany. Electronic address:
    Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Read More

    Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.
    Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.
    Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
    Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. Read More

    DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
    Am J Hum Genet 2017 Dec 30;101(6):888-902. Epub 2017 Nov 30.
    Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address:
    Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Read More

    A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.
    Am J Hum Genet 2017 Dec 30;101(6):995-1005. Epub 2017 Nov 30.
    School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia; Healthy Mothers and Babies, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address:
    A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p. Read More

    A Selection Operator for Summary Association Statistics Reveals Allelic Heterogeneity of Complex Traits.
    Am J Hum Genet 2017 Dec;101(6):903-912
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden; Center for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, Old Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland, United Kingdom. Electronic address:
    In recent years, as a secondary analysis in genome-wide association studies (GWASs), conditional and joint multiple-SNP analysis (GCTA-COJO) has been successful in allowing the discovery of additional association signals within detected loci. This suggests that many loci mapped in GWASs harbor more than a single causal variant. In order to interpret the underlying mechanism regulating a complex trait of interest in each discovered locus, researchers must assess the magnitude of allelic heterogeneity within the locus. Read More

    Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
    Am J Hum Genet 2017 Dec 30;101(6):1006-1012. Epub 2017 Nov 30.
    Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
    Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Read More

    Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.
    Am J Hum Genet 2017 Dec 30;101(6):913-924. Epub 2017 Nov 30.
    Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Anthropology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address:
    The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Read More

    The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and Post-admixture Selection in the Makranis of Pakistan.
    Am J Hum Genet 2017 Dec 9;101(6):977-984. Epub 2017 Nov 9.
    Unit of Human Evolutionary Genetics, Department of Genomes & Genetics, Institut Pasteur, Paris 75015, France; Centre National de la Recherche Scientifique URA3012, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France. Electronic address:
    From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. Read More

    Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells.
    Am J Hum Genet 2017 Dec 9;101(6):874-887. Epub 2017 Nov 9.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Neurological Research Institute, Houston, TX 77030, USA. Electronic address:
    Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Read More

    Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype.
    Am J Hum Genet 2017 Nov 26;101(5):824-832. Epub 2017 Oct 26.
    Department of Human Genetics, and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands. Electronic address:
    The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c. Read More

    Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression.
    Am J Hum Genet 2017 Nov 26;101(5):686-699. Epub 2017 Oct 26.
    Department of Genetics, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
    Previous studies have prioritized trait-relevant cell types by looking for an enrichment of genome-wide association study (GWAS) signal within functional regions. However, these studies are limited in cell resolution by the lack of functional annotations from difficult-to-characterize or rare cell populations. Measurement of single-cell gene expression has become a popular method for characterizing novel cell types, and yet limited work has linked single-cell RNA sequencing (RNA-seq) to phenotypes of interest. Read More

    Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.
    Am J Hum Genet 2017 Nov;101(5):856-865
    Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address:
    Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. Read More

    De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise.
    Am J Hum Genet 2017 Nov;101(5):844-855
    Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands.
    A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c. Read More

    De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.
    Am J Hum Genet 2017 Nov;101(5):833-843
    Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address:
    Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c. Read More

    Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".
    Am J Hum Genet 2017 Nov;101(5):815-823
    Centre Hospitalier Universitaire Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:
    Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. Read More

    Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice.
    Am J Hum Genet 2017 Nov;101(5):803-814
    Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address:
    Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. Read More

    Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.
    Am J Hum Genet 2017 Nov;101(5):789-802
    Division of Nephrology, Columbia University, New York, NY 10032, USA.
    Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. Read More

    De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.
    Am J Hum Genet 2017 Nov;101(5):768-788
    CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
    Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. Read More

    Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans.
    Am J Hum Genet 2017 Nov;101(5):752-767
    Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94702, USA; Museum of Natural History, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark; Department of Statistics, University of California, Berkeley, Berkeley, CA 94702, USA. Electronic address:
    The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. Read More

    Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits.
    Am J Hum Genet 2017 Nov;101(5):737-751
    Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90024, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA.
    Although genetic correlations between complex traits provide valuable insights into epidemiological and etiological studies, a precise quantification of which genomic regions disproportionately contribute to the genome-wide correlation is currently lacking. Here, we introduce ρ-HESS, a technique to quantify the correlation between pairs of traits due to genetic variation at a small region in the genome. Our approach requires GWAS summary data only and makes no distributional assumption on the causal variant effect sizes while accounting for linkage disequilibrium (LD) and overlapping GWAS samples. Read More

    Genome-wide Ancestry and Demographic History of African-Descendant Maroon Communities from French Guiana and Suriname.
    Am J Hum Genet 2017 Nov;101(5):725-736
    Laboratoire d'Anthropologie Moléculaire et Imagerie de Synthèse, AMIS UMR5288, Centre National de la Recherche Scientifique (CNRS) -Université Paul Sabatier Toulouse III, Toulouse 31000, France. Electronic address:
    The transatlantic slave trade was the largest forced migration in world history. However, the origins of the enslaved Africans and their admixture dynamics remain unclear. To investigate the demographic history of African-descendant Marron populations, we generated genome-wide data (4. Read More

    De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.
    Am J Hum Genet 2017 Nov;101(5):716-724
    Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address:
    DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. Read More

    Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.
    Am J Hum Genet 2017 Nov;101(5):700-715
    Human Longevity, San Diego, CA 92121, USA. Electronic address:
    Short tandem repeats (STRs) are hyper-mutable sequences in the human genome. They are often used in forensics and population genetics and are also the underlying cause of many genetic diseases. There are challenges associated with accurately determining the length polymorphism of STR loci in the genome by next-generation sequencing (NGS). Read More

    High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
    Am J Hum Genet 2017 Nov;101(5):664-685
    Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada. Electronic address:
    Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. Read More

    A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression.
    Am J Hum Genet 2017 Nov 19;101(5):643-663. Epub 2017 Oct 19.
    Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
    Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. Read More

    DOMINO: Using Machine Learning to Predict Genes Associated with Dominant Disorders.
    Am J Hum Genet 2017 Oct;101(4):623-629
    Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 9HN, UK. Electronic address:
    In contrast to recessive conditions with biallelic inheritance, identification of dominant (monoallelic) mutations for Mendelian disorders is more difficult, because of the abundance of benign heterozygous variants that act as massive background noise (typically, in a 400:1 excess ratio). To reduce this overflow of false positives in next-generation sequencing (NGS) screens, we developed DOMINO, a tool assessing the likelihood for a gene to harbor dominant changes. Unlike commonly-used predictors of pathogenicity, DOMINO takes into consideration features that are the properties of genes, rather than of variants. Read More

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