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    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 Nov 1. Epub 2017 Nov 1.
    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 Nov 4. Epub 2017 Nov 4.
    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 Oct 23. Epub 2017 Oct 23.
    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 Oct 23. Epub 2017 Oct 23.
    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

    Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.
    Am J Hum Genet 2017 Oct;101(4):590-602
    MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
    The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Read More

    The Contribution of Neanderthals to Phenotypic Variation in Modern Humans.
    Am J Hum Genet 2017 Oct;101(4):578-589
    Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany. Electronic address:
    Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans. Read More

    Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest.
    Am J Hum Genet 2017 Oct 28;101(4):609-615. Epub 2017 Sep 28.
    State Key Laboratory of Genetic Engineering, Zhongshan Hospital, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai 200032, China; Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address:
    Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Read More

    Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.
    Am J Hum Genet 2017 Oct 28;101(4):616-622. Epub 2017 Sep 28.
    Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address:
    Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11. Read More

    Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects.
    Am J Hum Genet 2017 Oct 28;101(4):552-563. Epub 2017 Sep 28.
    Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy. Electronic address:
    The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Read More

    FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases.
    Am J Hum Genet 2017 Oct 28;101(4):630-637. Epub 2017 Sep 28.
    UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Centre de Référence des Surdités Génétiques, Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France. Electronic address:
    Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. Read More

    The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.
    Am J Hum Genet 2017 Oct 28;101(4):564-577. Epub 2017 Sep 28.
    Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address:
    Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0. Read More

    Female Infertility Caused by Mutations in the Oocyte-Specific Translational Repressor PATL2.
    Am J Hum Genet 2017 Oct 28;101(4):603-608. Epub 2017 Sep 28.
    Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. Electronic address:
    Infertility is a relatively common disorder of the reproductive system and remains unexplained in many cases. In vitro fertilization techniques have uncovered previously unrecognized infertility phenotypes, including oocyte maturation arrest, the molecular etiology of which remains largely unknown. We report two families affected by female-limited infertility caused by oocyte maturation failure. Read More

    De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.
    Am J Hum Genet 2017 Oct 21;101(4):516-524. Epub 2017 Sep 21.
    Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address:
    Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. Read More

    Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features.
    Am J Hum Genet 2017 Oct 21;101(4):503-515. Epub 2017 Sep 21.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address:
    Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Read More

    Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.
    Am J Hum Genet 2017 Oct 21;101(4):525-538. Epub 2017 Sep 21.
    Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address:
    Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Read More

    Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport.
    Am J Hum Genet 2017 Oct 21;101(4):489-502. Epub 2017 Sep 21.
    Department of Genetics, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
    Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. Read More

    Prospects of Fine-Mapping Trait-Associated Genomic Regions by Using Summary Statistics from Genome-wide Association Studies.
    Am J Hum Genet 2017 Oct 21;101(4):539-551. Epub 2017 Sep 21.
    Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Department of Public Health, University of Helsinki, 00014 Helsinki, Finland; Helsinki Institute for Information Technology and Department of Mathematics and Statistics, University of Helsinki, 00014 Helsinki, Finland. Electronic address:
    During the past few years, various novel statistical methods have been developed for fine-mapping with the use of summary statistics from genome-wide association studies (GWASs). Although these approaches require information about the linkage disequilibrium (LD) between variants, there has not been a comprehensive evaluation of how estimation of the LD structure from reference genotype panels performs in comparison with that from the original individual-level GWAS data. Using population genotype data from Finland and the UK Biobank, we show here that a reference panel of 1,000 individuals from the target population is adequate for a GWAS cohort of up to 10,000 individuals, whereas smaller panels, such as those from the 1000 Genomes Project, should be avoided. Read More

    RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.
    Am J Hum Genet 2017 Sep;101(3):466-477
    Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address:
    RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Read More

    A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility.
    Am J Hum Genet 2017 Sep;101(3):459-465
    Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250001, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001, China; The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China. Electronic address:
    Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Read More

    Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44.
    Am J Hum Genet 2017 Sep;101(3):451-458
    Nuffield Department of Clinical Neurosciences, University of Oxford, 6th Floor West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK. Electronic address:
    The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias. Read More

    A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.
    Am J Hum Genet 2017 Sep;101(3):417-427
    Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7HE, UK; Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK; NIHR Biomedical Research Centre, NDORMS, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7HE, UK. Electronic address:
    Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. Read More

    CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays.
    Am J Hum Genet 2017 Sep;101(3):391-403
    Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; National University of Singapore, Department of Biochemistry, Singapore 117597, Republic of Singapore. Electronic address:
    In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. Read More

    Variant Interpretation: Functional Assays to the Rescue.
    Am J Hum Genet 2017 Sep;101(3):315-325
    Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA. Electronic address:
    Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Read More

    Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.
    Am J Hum Genet 2017 Sep 31;101(3):369-390. Epub 2017 Aug 31.
    Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:
    Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Read More

    Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes.
    Am J Hum Genet 2017 Sep 31;101(3):478-484. Epub 2017 Aug 31.
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands. Electronic address:
    Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Read More

    The Genetic Legacy of Zoroastrianism in Iran and India: Insights into Population Structure, Gene Flow, and Selection.
    Am J Hum Genet 2017 Sep 24;101(3):353-368. Epub 2017 Aug 24.
    Department Genetics, Evolution & Environment, University College London, London WC1E 6BT, UK. Electronic address:
    Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Read More

    A Scalable Bayesian Method for Integrating Functional Information in Genome-wide Association Studies.
    Am J Hum Genet 2017 Sep 24;101(3):404-416. Epub 2017 Aug 24.
    Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA. Electronic address:
    Genome-wide association studies (GWASs) have identified many complex loci. However, most loci reside in noncoding regions and have unknown biological functions. Integrative analysis that incorporates known functional information into GWASs can help elucidate the underlying biological mechanisms and prioritize important functional variants. Read More

    Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping.
    Am J Hum Genet 2017 Sep 24;101(3):326-339. Epub 2017 Aug 24.
    Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address:
    During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Read More

    Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data.
    Am J Hum Genet 2017 Sep 24;101(3):340-352. Epub 2017 Aug 24.
    Department of Biostatistics, Columbia University, New York, NY 10032, USA. Electronic address:
    Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Read More

    Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development.
    Am J Hum Genet 2017 Sep 17;101(3):428-440. Epub 2017 Aug 17.
    Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France. Electronic address:
    Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. Read More

    Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.
    Am J Hum Genet 2017 Sep 17;101(3):441-450. Epub 2017 Aug 17.
    Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA. Electronic address:
    Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. Read More

    De Novo Mutations in YWHAG Cause Early-Onset Epilepsy.
    Am J Hum Genet 2017 Aug;101(2):300-310
    Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC V5R 6H8, Canada. Electronic address:
    Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Read More

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