11,433 results match your criteria American journal of human genetics[Journal]


Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.

Am J Hum Genet 2019 Feb 8. Epub 2019 Feb 8.

Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address:

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.009DOI Listing
February 2019

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

Am J Hum Genet 2019 Feb 11. Epub 2019 Feb 11.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.007DOI Listing
February 2019

Genome-wide Significance Thresholds for Admixture Mapping Studies.

Am J Hum Genet 2019 Feb 4. Epub 2019 Feb 4.

Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193000
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http://dx.doi.org/10.1016/j.ajhg.2019.01.008DOI Listing
February 2019
1 Read

Practical and Ethical Considerations of Using Personal DNA Tests with Middle-School-Aged Learners.

Am J Hum Genet 2019 Feb;104(2):197-202

Anthropology Department, The Pennsylvania State University, State College, PA 16802, USA.

Personalized genetic information is not widely utilized as a resource in learning environments, in part because of concerns about data privacy and the treatment of sensitive personal information. Here we describe the implementation of a curriculum centered on analyzing personalized genetic-ancestry test results during two-week science summer camps for middle-school-aged youth. Our research focused on how the examination of personalized DNA results affected learners' subsequent perceptions and performance, as measured by in-camp pre- and post-tests and surveys, analysis of voluntary student talk captured by audio and video recordings, and periodic one-on-one post-camp follow-ups. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.001DOI Listing
February 2019

Optimal Integration of Behavioral Medicine into Clinical Genetics and Genomics.

Am J Hum Genet 2019 Feb;104(2):193-196

Department of Community Sciences, Boston University School of Public Health, Boston, MA 02118, USA.

Clinical genetics and genomics will exert their greatest population impact by leveraging the rich knowledge of human behavior that is central to the discipline of behavioral medicine. We contend that more concerted efforts are needed to integrate these fields synergistically, and accordingly, we consider barriers and potential actions to hasten such integration. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193001
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http://dx.doi.org/10.1016/j.ajhg.2019.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369539PMC
February 2019
2 Reads

Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria.

Am J Hum Genet 2019 Feb 31;104(2):341-347. Epub 2019 Jan 31.

Centre de Recherches sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale U1149, 75018 Paris, France; Université Paris Diderot, 75018 Paris, France; Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, 178 rue des Renouillers, 92701 Colombes, France; Laboratory of Excellence GR-Ex, 75015 Paris, France. Electronic address:

Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369449PMC
February 2019
1 Read

Improved Pathogenic Variant Localization via a Hierarchical Model of Sub-regional Intolerance.

Am J Hum Genet 2019 Feb 24;104(2):299-309. Epub 2019 Jan 24.

Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Division of Integrative Genomics, Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA; Duke Center for Statistical Genetics and Genomics, Duke University, Durham, NC 27710, USA. Electronic address:

Different parts of a gene can be of differential importance to development and health. This regional heterogeneity is also apparent in the distribution of disease-associated mutations, which often cluster in particular regions of disease-associated genes. The ability to precisely estimate functionally important sub-regions of genes will be key in correctly deciphering relationships between genetic variation and disease. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369453PMC
February 2019

Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice.

Am J Hum Genet 2019 Feb 24;104(2):331-340. Epub 2019 Jan 24.

Team Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, Université Grenoble Alpes, Inserm U1209, Centre National de la Recherche Scientifique UMR 5309, Grenoble 38000, France; Unité Médicale de génétique de l'infertilité et de diagnostic pré-implantatoire (GI-DPI), Centre Hospitalier Universitaire Grenoble Alpes, Grenoble 38000, France. Electronic address:

Male infertility is a major health concern. Among its different causes, multiple morphological abnormalities of the flagella (MMAF) induces asthenozoospermia and is one of the most severe forms of qualitative sperm defects. Sperm of affected men display short, coiled, absent, and/or irregular flagella. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.013DOI Listing
February 2019

Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness.

Am J Hum Genet 2019 Feb 24;104(2):310-318. Epub 2019 Jan 24.

Division of Neonatology, Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA; McPherson Eye Research, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address:

Pathogenic variants of the KCNJ13 gene are known to cause Leber congenital amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 encodes the Kir7.1 subunit that acts as a tetrameric, inwardly rectifying potassium ion channel in the retinal pigment epithelium (RPE) to maintain ionic homeostasis and allow photoreceptors to encode visual information. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369573PMC
February 2019

Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.

Am J Hum Genet 2019 Feb 18;104(2):229-245. Epub 2019 Jan 18.

Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.009DOI Listing
February 2019
4 Reads

Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.

Am J Hum Genet 2019 Feb 18;104(2):275-286. Epub 2019 Jan 18.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Research, Innovation, Learning and Development building, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. Electronic address:

More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183046
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http://dx.doi.org/10.1016/j.ajhg.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369448PMC
February 2019
4 Reads
10.931 Impact Factor

De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.

Am J Hum Genet 2019 Feb 17;104(2):246-259. Epub 2019 Jan 17.

Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369454PMC
February 2019
3 Reads
10.931 Impact Factor

Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.

Am J Hum Genet 2019 Feb 17;104(2):287-298. Epub 2019 Jan 17.

Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. Electronic address:

Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369575PMC
February 2019
2 Reads

TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways.

Am J Hum Genet 2019 Feb 17;104(2):348-355. Epub 2019 Jan 17.

Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, 75015 Paris, France; Department of Genetics, Reference center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP,75015 Paris, France. Electronic address:

Steroid-resistant nephrotic syndrome (SRNS) is characterized by high-range proteinuria and most often focal and segmental glomerulosclerosis (FSGS). Identification of mutations in genes causing SRNS has improved our understanding of disease mechanisms and highlighted defects in the podocyte, a highly specialized glomerular epithelial cell, as major factors in disease pathogenesis. By exome sequencing, we identified missense mutations in TBC1D8B in two families with an X-linked early-onset SRNS with FSGS. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369567PMC
February 2019
3 Reads
10.931 Impact Factor

Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.

Am J Hum Genet 2019 Feb 10;104(2):260-274. Epub 2019 Jan 10.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Statistics, Harvard University, Cambridge, MA 02138, USA. Electronic address:

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.012DOI Listing
February 2019
3 Reads

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 Feb 10;104(2):213-228. Epub 2019 Jan 10.

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA; Institute of Mother and Child, 01-211 Warsaw, Poland. Electronic address:

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183046
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019
6 Reads

ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

Am J Hum Genet 2019 Feb 10;104(2):319-330. Epub 2019 Jan 10.

Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091 Strasbourg, France. Electronic address:

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369415PMC
February 2019
3 Reads

De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.

Am J Hum Genet 2019 Feb 3;104(2):203-212. Epub 2019 Jan 3.

Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany.

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183045
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http://dx.doi.org/10.1016/j.ajhg.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369540PMC
February 2019
10 Reads

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies.

Am J Hum Genet 2019 Jan;104(1):94-111

Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA. Electronic address:

The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323578PMC
January 2019
1 Read

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Am J Hum Genet 2019 Jan;104(1):76-93

Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323417PMC
January 2019
2 Reads

Prohibiting Genetic Discrimination to Promote Science, Health, and Fairness.

Authors:

Am J Hum Genet 2019 Jan;104(1):6-7

Protections against genetic discrimination advance genetics research and the clinical use of genetics, as well as ensure the ethical use of genetic data. Ten years after the passage of the Genetic Information Nondiscrimination Act (GINA), the American Society of Human Genetics remains a staunch advocate for GINA's strong implementation and for other laws that enhance protections for the public. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323607PMC
January 2019
1 Read

Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy.

Am J Hum Genet 2019 Jan;104(1):45-54

Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183040
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http://dx.doi.org/10.1016/j.ajhg.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323550PMC
January 2019
9 Reads

Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture.

Am J Hum Genet 2019 Jan;104(1):187-190

Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323549PMC
January 2019
3 Reads

Response to Whiffin et al.

Am J Hum Genet 2019 Jan;104(1):186

The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323415PMC
January 2019
2 Reads

Integrating Genomics into Healthcare: A Global Responsibility.

Am J Hum Genet 2019 Jan;104(1):13-20

Australian Genomics Health Alliance, Melbourne VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne VIC 3052, Australia; Global Alliance for Genomics and Health, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada. Electronic address:

Genomic sequencing is rapidly transitioning into clinical practice, and implementation into healthcare systems has been supported by substantial government investment, totaling over US$4 billion, in at least 14 countries. These national genomic-medicine initiatives are driving transformative change under real-life conditions while simultaneously addressing barriers to implementation and gathering evidence for wider adoption. We review the diversity of approaches and current progress made by national genomic-medicine initiatives in the UK, France, Australia, and US and provide a roadmap for sharing strategies, standards, and data internationally to accelerate implementation. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323624PMC
January 2019
5 Reads

Human-Disease Phenotype Map Derived from PheWAS across 38,682 Individuals.

Am J Hum Genet 2019 Jan 29;104(1):55-64. Epub 2018 Dec 29.

The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Biomedical and Translational Informatics Institute, Geisinger, Danville, PA 17821, USA. Electronic address:

Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323551PMC
January 2019
3 Reads
10.931 Impact Factor

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Authors:
Aldi T Kraja Chunyu Liu Jessica L Fetterman Mariaelisa Graff Christian Theil Have Charles Gu Lisa R Yanek Mary F Feitosa Dan E Arking Daniel I Chasman Kristin Young Symen Ligthart W David Hill Stefan Weiss Jian'an Luan Franco Giulianini Ruifang Li-Gao Fernando P Hartwig Shiow J Lin Lihua Wang Tom G Richardson Jie Yao Eliana P Fernandez Mohsen Ghanbari Mary K Wojczynski Wen-Jane Lee Maria Argos Sebastian M Armasu Ruteja A Barve Kathleen A Ryan Ping An Thomas J Baranski Suzette J Bielinski Donald W Bowden Ulrich Broeckel Kaare Christensen Audrey Y Chu Janie Corley Simon R Cox Andre G Uitterlinden Fernando Rivadeneira Cheryl D Cropp E Warwick Daw Diana van Heemst Lisa de Las Fuentes He Gao Ioanna Tzoulaki Tarunveer S Ahluwalia Renée de Mutsert Leslie S Emery A Mesut Erzurumluoglu James A Perry Mao Fu Nita G Forouhi Zhenglong Gu Yang Hai Sarah E Harris Gibran Hemani Steven C Hunt Marguerite R Irvin Anna E Jonsson Anne E Justice Nicola D Kerrison Nicholas B Larson Keng-Hung Lin Latisha D Love-Gregory Rasika A Mathias Joseph H Lee Matthias Nauck Raymond Noordam Ken K Ong James Pankow Amit Patki Alison Pattie Astrid Petersmann Qibin Qi Rasmus Ribel-Madsen Rebecca Rohde Kevin Sandow Theresia M Schnurr Tamar Sofer John M Starr Adele M Taylor Alexander Teumer Nicholas J Timpson Hugoline G de Haan Yujie Wang Peter E Weeke Christine Williams Hongsheng Wu Wei Yang Donglin Zeng Daniel R Witte Bruce S Weir Nicholas J Wareham Henrik Vestergaard Stephen T Turner Christian Torp-Pedersen Evie Stergiakouli Wayne Huey-Herng Sheu Frits R Rosendaal M Arfan Ikram Oscar H Franco Paul M Ridker Thomas T Perls Oluf Pedersen Ellen A Nohr Anne B Newman Allan Linneberg Claudia Langenberg Tuomas O Kilpeläinen Sharon L R Kardia Marit E Jørgensen Torben Jørgensen Thorkild I A Sørensen Georg Homuth Torben Hansen Mark O Goodarzi Ian J Deary Cramer Christensen Yii-Der Ida Chen Aravinda Chakravarti Ivan Brandslund Klaus Bonnelykke Kent D Taylor James G Wilson Santiago Rodriguez Gail Davies Bernardo L Horta Bharat Thyagarajan D C Rao Niels Grarup Victor G Davila-Roman Gavin Hudson Xiuqing Guo Donna K Arnett Caroline Hayward Dhananjay Vaidya Dennis O Mook-Kanamori Hemant K Tiwari Daniel Levy Ruth J F Loos Abbas Dehghan Paul Elliott Afshan N Malik Robert A Scott Diane M Becker Mariza de Andrade Michael A Province James B Meigs Jerome I Rotter Kari E North

Am J Hum Genet 2019 Jan 27;104(1):112-138. Epub 2018 Dec 27.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA. Electronic address:

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019
9 Reads

De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders.

Am J Hum Genet 2019 Jan 27;104(1):139-156. Epub 2018 Dec 27.

Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address:

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323609PMC
January 2019
4 Reads

Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive.

Am J Hum Genet 2019 Jan 27;104(1):179-185. Epub 2018 Dec 27.

Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address:

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323416PMC
January 2019
2 Reads

Leveraging Polygenic Functional Enrichment to Improve GWAS Power.

Am J Hum Genet 2019 Jan 27;104(1):65-75. Epub 2018 Dec 27.

Department of Epidemiology. Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address:

Functional genomics data has the potential to increase GWAS power by identifying SNPs that have a higher prior probability of association. Here, we introduce a method that leverages polygenic functional enrichment to incorporate coding, conserved, regulatory, and LD-related genomic annotations into association analyses. We show via simulations with real genotypes that the method, functionally informed novel discovery of risk loci (FINDOR), correctly controls the false-positive rate at null loci and attains a 9%-38% increase in the number of independent associations detected at causal loci, depending on trait polygenicity and sample size. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323418PMC
January 2019
1 Read
10.931 Impact Factor

GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.

Am J Hum Genet 2019 Jan 21;104(1):157-163. Epub 2018 Dec 21.

National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Old Road, Oxford OX3 7LE, UK; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Big Data Institute Building, Roosevelt Drive, University of Oxford, Oxford OX3 7LF, UK; Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323625PMC
January 2019
2 Reads

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Am J Hum Genet 2019 Jan 20;104(1):164-178. Epub 2018 Dec 20.

Department of Pediatrics, CHU Sainte-Justine Research Center and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183041
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http://dx.doi.org/10.1016/j.ajhg.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323608PMC
January 2019
10 Reads
10.931 Impact Factor

GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome.

Am J Hum Genet 2019 Jan 13;104(1):35-44. Epub 2018 Dec 13.

Nemours Biomedical Research Department, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address:

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323552PMC
January 2019
1 Read

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Authors:
Nasim Mavaddat Kyriaki Michailidou Joe Dennis Michael Lush Laura Fachal Andrew Lee Jonathan P Tyrer Ting-Huei Chen Qin Wang Manjeet K Bolla Xin Yang Muriel A Adank Thomas Ahearn Kristiina Aittomäki Jamie Allen Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Volker Arndt Kristan J Aronson Paul L Auer Päivi Auvinen Myrto Barrdahl Laura E Beane Freeman Matthias W Beckmann Sabine Behrens Javier Benitez Marina Bermisheva Leslie Bernstein Carl Blomqvist Natalia V Bogdanova Stig E Bojesen Bernardo Bonanni Anne-Lise Børresen-Dale Hiltrud Brauch Michael Bremer Hermann Brenner Adam Brentnall Ian W Brock Angela Brooks-Wilson Sara Y Brucker Thomas Brüning Barbara Burwinkel Daniele Campa Brian D Carter Jose E Castelao Stephen J Chanock Rowan Chlebowski Hans Christiansen Christine L Clarke J Margriet Collée Emilie Cordina-Duverger Sten Cornelissen Fergus J Couch Angela Cox Simon S Cross Kamila Czene Mary B Daly Peter Devilee Thilo Dörk Isabel Dos-Santos-Silva Martine Dumont Lorraine Durcan Miriam Dwek Diana M Eccles Arif B Ekici A Heather Eliassen Carolina Ellberg Christoph Engel Mikael Eriksson D Gareth Evans Peter A Fasching Jonine Figueroa Olivia Fletcher Henrik Flyger Asta Försti Lin Fritschi Marike Gabrielson Manuela Gago-Dominguez Susan M Gapstur José A García-Sáenz Mia M Gaudet Vassilios Georgoulias Graham G Giles Irina R Gilyazova Gord Glendon Mark S Goldberg David E Goldgar Anna González-Neira Grethe I Grenaker Alnæs Mervi Grip Jacek Gronwald Anne Grundy Pascal Guénel Lothar Haeberle Eric Hahnen Christopher A Haiman Niclas Håkansson Ute Hamann Susan E Hankinson Elaine F Harkness Steven N Hart Wei He Alexander Hein Jane Heyworth Peter Hillemanns Antoinette Hollestelle Maartje J Hooning Robert N Hoover John L Hopper Anthony Howell Guanmengqian Huang Keith Humphreys David J Hunter Milena Jakimovska Anna Jakubowska Wolfgang Janni Esther M John Nichola Johnson Michael E Jones Arja Jukkola-Vuorinen Audrey Jung Rudolf Kaaks Katarzyna Kaczmarek Vesa Kataja Renske Keeman Michael J Kerin Elza Khusnutdinova Johanna I Kiiski Julia A Knight Yon-Dschun Ko Veli-Matti Kosma Stella Koutros Vessela N Kristensen Ute Krüger Tabea Kühl Diether Lambrechts Loic Le Marchand Eunjung Lee Flavio Lejbkowicz Jenna Lilyquist Annika Lindblom Sara Lindström Jolanta Lissowska Wing-Yee Lo Sibylle Loibl Jirong Long Jan Lubiński Michael P Lux Robert J MacInnis Tom Maishman Enes Makalic Ivana Maleva Kostovska Arto Mannermaa Siranoush Manoukian Sara Margolin John W M Martens Maria Elena Martinez Dimitrios Mavroudis Catriona McLean Alfons Meindl Usha Menon Pooja Middha Nicola Miller Fernando Moreno Anna Marie Mulligan Claire Mulot Victor M Muñoz-Garzon Susan L Neuhausen Heli Nevanlinna Patrick Neven William G Newman Sune F Nielsen Børge G Nordestgaard Aaron Norman Kenneth Offit Janet E Olson Håkan Olsson Nick Orr V Shane Pankratz Tjoung-Won Park-Simon Jose I A Perez Clara Pérez-Barrios Paolo Peterlongo Julian Peto Mila Pinchev Dijana Plaseska-Karanfilska Eric C Polley Ross Prentice Nadege Presneau Darya Prokofyeva Kristen Purrington Katri Pylkäs Brigitte Rack Paolo Radice Rohini Rau-Murthy Gad Rennert Hedy S Rennert Valerie Rhenius Mark Robson Atocha Romero Kathryn J Ruddy Matthias Ruebner Emmanouil Saloustros Dale P Sandler Elinor J Sawyer Daniel F Schmidt Rita K Schmutzler Andreas Schneeweiss Minouk J Schoemaker Fredrick Schumacher Peter Schürmann Lukas Schwentner Christopher Scott Rodney J Scott Caroline Seynaeve Mitul Shah Mark E Sherman Martha J Shrubsole Xiao-Ou Shu Susan Slager Ann Smeets Christof Sohn Penny Soucy Melissa C Southey John J Spinelli Christa Stegmaier Jennifer Stone Anthony J Swerdlow Rulla M Tamimi William J Tapper Jack A Taylor Mary Beth Terry Kathrin Thöne Rob A E M Tollenaar Ian Tomlinson Thérèse Truong Maria Tzardi Hans-Ulrich Ulmer Michael Untch Celine M Vachon Elke M van Veen Joseph Vijai Clarice R Weinberg Camilla Wendt Alice S Whittemore Hans Wildiers Walter Willett Robert Winqvist Alicja Wolk Xiaohong R Yang Drakoulis Yannoukakos Yan Zhang Wei Zheng Argyrios Ziogas Alison M Dunning Deborah J Thompson Georgia Chenevix-Trench Jenny Chang-Claude Marjanka K Schmidt Per Hall Roger L Milne Paul D P Pharoah Antonis C Antoniou Nilanjan Chatterjee Peter Kraft Montserrat García-Closas Jacques Simard Douglas F Easton

Am J Hum Genet 2019 Jan 13;104(1):21-34. Epub 2018 Dec 13.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183040
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http://dx.doi.org/10.1016/j.ajhg.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323553PMC
January 2019
24 Reads
10.931 Impact Factor

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism.

Am J Hum Genet 2018 Dec;103(6):948-967

Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; NIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288279PMC
December 2018
2 Reads

The Genetic Ancestry of Modern Indus Valley Populations from Northwest India.

Am J Hum Genet 2018 Dec;103(6):918-929

Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.

The Indus Valley has been the backdrop for several historic and prehistoric population movements between South Asia and West Eurasia. However, the genetic structure of present-day populations from Northwest India is poorly characterized. Here we report new genome-wide genotype data for 45 modern individuals from four Northwest Indian populations, including the Ror, whose long-term occupation of the region can be traced back to the early Vedic scriptures. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288199PMC
December 2018
1 Read
10.931 Impact Factor

Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies.

Am J Hum Genet 2018 Dec;103(6):893-906

McGill University and Genome Quebec Innovation Centre, Montréal, QC H3A 0G1, Canada. Electronic address:

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288464PMC
December 2018
1 Read

Human Models Are Needed for Studying Human Neurodevelopmental Disorders.

Am J Hum Genet 2018 Dec;103(6):829-857

Waisman Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53705, USA; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53705, USA. Electronic address:

The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288051PMC
December 2018
1 Read

Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies.

Am J Hum Genet 2018 Dec;103(6):1022-1029

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address:

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183039
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http://dx.doi.org/10.1016/j.ajhg.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288405PMC
December 2018
2 Reads

The Genetic Landscape of Diamond-Blackfan Anemia.

Am J Hum Genet 2018 Dec 29;103(6):930-947. Epub 2018 Nov 29.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288280PMC
December 2018
5 Reads

Parkinson-Associated SNCA Enhancer Variants Revealed by Open Chromatin in Mouse Dopamine Neurons.

Am J Hum Genet 2018 Dec 29;103(6):874-892. Epub 2018 Nov 29.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD), and modulation of risk by common variants in PD has been well established through genome-wide association studies (GWASs). We acquired open chromatin signatures of purified embryonic mouse MB DA neurons because we anticipated that a fraction of PD-associated genetic variation might mediate the variants' effects within this neuronal population. Correlation with >2,300 putative enhancers assayed in mice revealed enrichment for MB cis-regulatory elements (CREs), and these data were reinforced by transgenic analyses of six additional sequences in zebrafish and mice. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288322PMC
December 2018
12 Reads

OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data.

Am J Hum Genet 2018 Dec 29;103(6):907-917. Epub 2018 Nov 29.

Department of Informatics, Technical University of Munich, Boltzmannstr. 3, 85748 Garching, Germany; Quantitative Biosciences Munich, Gene Center, Department of Biochemistry, Ludwig-Maximilians Universität München, Feodor-Lynen-Str. 25, 81377 München, Germany. Electronic address:

RNA sequencing (RNA-seq) is gaining popularity as a complementary assay to genome sequencing for precisely identifying the molecular causes of rare disorders. A powerful approach is to identify aberrant gene expression levels as potential pathogenic events. However, existing methods for detecting aberrant read counts in RNA-seq data either lack assessments of statistical significance, so that establishing cutoffs is arbitrary, or rely on subjective manual corrections for confounders. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183040
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http://dx.doi.org/10.1016/j.ajhg.2018.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288422PMC
December 2018
16 Reads

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

Am J Hum Genet 2018 Dec 29;103(6):1038-1044. Epub 2018 Nov 29.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address:

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288413PMC
December 2018
5 Reads

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.

Am J Hum Genet 2018 Dec 29;103(6):1030-1037. Epub 2018 Nov 29.

Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Read More

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http://dx.doi.org/10.1016/j.ajhg.2018.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288200PMC
December 2018
13 Reads

Detecting Expansions of Tandem Repeats in Cohorts Sequenced with Short-Read Sequencing Data.

Am J Hum Genet 2018 Dec 29;103(6):858-873. Epub 2018 Nov 29.

Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne 3010, VIC, Australia. Electronic address:

Repeat expansions cause more than 30 inherited disorders, predominantly neurogenetic. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single-gene or small-panel PCR-based methods can help to identify the precise genetic cause, but they can be slow and costly and often yield no result. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297183036
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http://dx.doi.org/10.1016/j.ajhg.2018.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288141PMC
December 2018
10 Reads