Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging
Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 22, 2019 Category: Genetics & Stem Cells Authors: Elisabetta Flex, Simone Martinelli, Anke Van Dijck, Andrea Ciolfi, Serena Cecchetti, Elisa Coluzzi, Luca Pannone, Cristina Andreoli, Francesca Clementina Radio, Simone Pizzi, Giovanna Carpentieri, Alessandro Bruselles, Giuseppina Catanzaro, Lucia Pedace, Tags: Article Source Type: research

Pathogenic Abnormal Splicing due to Intronic Deletions that Induce Biophysical Space Constraint for Spliceosome Assembly
A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-co...
Source: The American Journal of Human Genetics - August 22, 2019 Category: Genetics & Stem Cells Authors: Samantha J. Bryen, Himanshu Joshi, Frances J. Evesson, Cyrille Girard, Roula Ghaoui, Leigh B. Waddell, Alison C. Testa, Beryl Cummings, Susan Arbuckle, Nicole Graf, Richard Webster, Daniel G. MacArthur, Nigel G. Laing, Mark R. Davis, Reinhard L ührmann, Tags: Article Source Type: research

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis
FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T  cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 22, 2019 Category: Genetics & Stem Cells Authors: Marita Bosticardo, Yasuhiro Yamazaki, Jennifer Cowan, Giuliana Giardino, Cristina Corsino, Giulia Scalia, Rosaria Prencipe, Melanie Ruffner, David A. Hill, Inga Sakovich, Irma Yemialyanava, Jonathan S. Tam, Nurcicek Padem, Melissa E. Elder, John W. Sleasm Tags: Article Source Type: research

Using Transcriptomic Hidden Variables to Infer Context-Specific Genotype Effects in the Brain
Deciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). (Source: ...
Source: The American Journal of Human Genetics - August 22, 2019 Category: Genetics & Stem Cells Authors: Bernard Ng, William Casazza, Ellis Patrick, Shinya Tasaki, Gherman Novakovsky, Daniel Felsky, Yiyi Ma, David A. Bennett, Chris Gaiteri, Philip L. De Jager, Sara Mostafavi Tags: Article Source Type: research

Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network
The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled>25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery,...
Source: The American Journal of Human Genetics - August 22, 2019 Category: Genetics & Stem Cells Authors: The eMERGE Consortium Tags: Article Source Type: research

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation
The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicant...
Source: The American Journal of Human Genetics - August 15, 2019 Category: Genetics & Stem Cells Authors: Chris Balak, Marianne Benard, Elise Schaefer, Sumaiya Iqbal, Keri Ramsey, Mich èle Ernoult-Lange, Francesca Mattioli, Lorida Llaci, Véronique Geoffroy, Maité Courel, Marcus Naymik, Kristine K. Bachman, Rolph Pfundt, Patrick Rump, Johanna ter Beest, Ing Tags: Article Source Type: research

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting
As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable...
Source: The American Journal of Human Genetics - August 15, 2019 Category: Genetics & Stem Cells Authors: Adam S. Gordon, Elisabeth A. Rosenthal, David S. Carrell, Laura M. Amendola, Michael O. Dorschner, Aaron Scrol, Ian B. Stanaway, Shannon DeVange, James D. Ralston, Hana Zouk, Heidi L. Rehm, Eric Larson, David R. Crosslin, Kathy A. Leppig, Gail P. Jarvik Tags: Article Source Type: research

Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy
Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 15, 2019 Category: Genetics & Stem Cells Authors: Clara D.M. van Karnebeek, R úben J. Ramos, Xiao-Yan Wen, Maja Tarailo-Graovac, Joseph G. Gleeson, Cristina Skrypnyk, Koroboshka Brand-Arzamendi, Farhad Karbassi, Mahmoud Y. Issa, Robin van der Lee, Britt I. Drögemöller, Janet Koster, Justine Rousseau, Tags: Article Source Type: research

Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection —purging large-effect mutations in these regions—leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 8, 2019 Category: Genetics & Stem Cells Authors: Luke J. O'Connor, Armin P. Schoech, Farhad Hormozdiari, Steven Gazal, Nick Patterson, Alkes L. Price Tags: Article Source Type: research

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies
The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. (Source: T...
Source: The American Journal of Human Genetics - August 8, 2019 Category: Genetics & Stem Cells Authors: Richard J. Holt, Rodrigo M. Young, Berta Crespo, Fabiola Ceroni, Cynthia J. Curry, Emanuele Bellacchio, Dorine A. Bax, Andrea Ciolfi, Marleen Simon, Christina R. Fagerberg, Ellen van Binsbergen, Alessandro De Luca, Luigi Memo, William B. Dobyns, Alaa Afif Tags: Report Source Type: research

Identifying Putative Susceptibility Genes and Evaluating Their Associations with Somatic Mutations in Human Cancers
Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer —colorectal, lung, ovary, prostate, pancreas, and melanoma—by using transcriptome data from the Genotype-Tissue Expression (GTEx) Pr...
Source: The American Journal of Human Genetics - August 8, 2019 Category: Genetics & Stem Cells Authors: Zhishan Chen, Wanqing Wen, Alicia Beeghly-Fadiel, Xiao-ou Shu, Virginia D íez-Obrero, Jirong Long, Jiandong Bao, Jing Wang, Qi Liu, Qiuyin Cai, Victor Moreno, Wei Zheng, Xingyi Guo Tags: Article Source Type: research

DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging
Genetic information is constantly being attacked by intrinsic and extrinsic damaging agents, such as reactive oxygen species, atmospheric radiation, environmental chemicals, and chemotherapeutics. If DNA modifications persist, they can adversely affect the polymerization of DNA or RNA, leading to replication fork collapse or transcription arrest, or can serve as mutagenic templates during nucleic acid synthesis reactions. To combat the deleterious consequences of DNA damage, organisms have developed complex repair networks that remove chemical modifications or aberrant base arrangements and restore the genome to its origin...
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Vinod Tiwari, David M. Wilson Tags: Review Source Type: research

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways
Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Max Lam, W. David Hill, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, Eli Stahl, Laura Huckins, David C. Liewald, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Tags: Article Source Type: research

Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype
Brittle and “tiger-tail” hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differen tiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaire d nucleo...
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Arjan F. Theil, Elena Botta, Anja Raams, Desiree E.C. Smith, Marisa I. Mendes, Giuseppina Caligiuri, Sarah Giachetti, Silvia Bione, Roberta Carriero, Giordano Liberi, Luca Zardoni, Sigrid M.A. Swagemakers, Gajja S. Salomons, Alain Sarasin, Alan Lehmann, P Tags: Report Source Type: research

This Month in The Journal
For many years, the primary approach for studying complex genetic traits has been the genome-wide association study (GWAS). More recently, reasoning that gene expression patterns might provide deeper insight into the biology underlying a trait of interest, investigators have begun to turn to transcriptome-wide association studies (TWASs). A TWAS integrates eQTL analysis with GWAS to identify genes whose genetically regulated expression associates with a given trait or disease risk. The resultant list of prioritized genes (and tissues) can then be used for developing and testing hypotheses related to the phenotype of intere...
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Using the Data We Have: Improving Diversity in Genomic Research
The shortage of genomic research data in persons of non-European ancestry is impeding our ability to use genomics in the clinical care of non-European individuals. Improved efforts to utilize data on non-European populations will increase the quality of genomic research and the inferences drawn from it for people of all backgrounds. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Teri A. Manolio Tags: Forum Source Type: research

Genes for Good: Engaging the Public in Genetics Research via Social Media
(The American Journal of Human Genetics 105, 65 –77; July 3, 2019) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 1, 2019 Category: Genetics & Stem Cells Authors: Katharine Brieger, Gregory J.M. Zajac, Anita Pandit, Johanna R. Foerster, Kevin W. Li, Aubrey C. Annis, Ellen M. Schmidt, Chris P. Clark, Karly McMorrow, Wei Zhou, Jingjing Yang, Alan M. Kwong, Andrew P. Boughton, Jinxi Wu, Chris Scheller, Tanvi Parikh, A Tags: Correction Source Type: research

Phenome-wide Burden of Copy-Number Variation in the UK Biobank
Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses f...
Source: The American Journal of Human Genetics - July 25, 2019 Category: Genetics & Stem Cells Authors: Matthew Aguirre, Manuel A. Rivas, James Priest Tags: Article Source Type: research

Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies
The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GP...
Source: The American Journal of Human Genetics - July 25, 2019 Category: Genetics & Stem Cells Authors: Alexej Knaus, Fanny Kort üm, Tjitske Kleefstra, Asbjørg Stray-Pedersen, Dejan Đukić, Yoshiko Murakami, Thorsten Gerstner, Hans van Bokhoven, Zafar Iqbal, Denise Horn, Taroh Kinoshita, Maja Hempel, Peter M. Krawitz Tags: Report Source Type: research

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia
The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model sy stem, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 25, 2019 Category: Genetics & Stem Cells Authors: Hanneke A. Haijes, Maria J.E. Koster, Holger Rehmann, Dong Li, Hakon Hakonarson, Gerarda Cappuccio, Miroslava Hancarova, Daphne Lehalle, Willie Reardon, G. Bradley Schaefer, Anna Lehman, Ingrid M.B.H. van de Laar, Coranne D. Tesselaar, Clesson Turner, Ali Tags: Article Source Type: research

Phenome-wide Burden of Copy Number Variation in the UK Biobank
Copy number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses f...
Source: The American Journal of Human Genetics - July 25, 2019 Category: Genetics & Stem Cells Authors: Matthew Aguirre, Manuel A. Rivas, James Priest Tags: Article Source Type: research

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders
Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 25, 2019 Category: Genetics & Stem Cells Authors: Bj örn Fischer-Zirnsak, Lara Segebrecht, Max Schubach, Perrine Charles, Emily Alderman, Kathleen Brown, Maxime Cadieux-Dion, Tracy Cartwright, Yanmin Chen, Carrie Costin, Sarah Fehr, Keely M. Fitzgerald, Emily Fleming, Kimberly Foss, Thoa Ha, Gabriele Hi Tags: Report Source Type: research

Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 18, 2019 Category: Genetics & Stem Cells Authors: Epi25 Collaborative Tags: Article Source Type: research

Family Clustering of Autoimmune Vitiligo Results Principally from Polygenic Inheritance of Common Risk Alleles
Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are “simplex,” where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some “multiplex” families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with differ en...
Source: The American Journal of Human Genetics - July 18, 2019 Category: Genetics & Stem Cells Authors: Genevieve H.L. Roberts, Subrata Paul, Daniel Yorgov, Stephanie A. Santorico, Richard A. Spritz Tags: Article Source Type: research

De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 18, 2019 Category: Genetics & Stem Cells Authors: Oguz Kanca, Jonathan C. Andrews, Pei-Tseng Lee, Chirag Patel, Stephen R. Braddock, Anne M. Slavotinek, Julie S. Cohen, Cynthia S. Gubbels, Kimberly A. Aldinger, Judy Williams, Maanasa Indaram, Ali Fatemi, Timothy W. Yu, Pankaj B. Agrawal, Gilbert Vezina, Tags: Report Source Type: research

De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome
While genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using exome-sequencing analysis and review of matchmaker databases, we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37 —p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile—in unrelated individuals with a previously unrecognized syndrome. Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; si...
Source: The American Journal of Human Genetics - July 18, 2019 Category: Genetics & Stem Cells Authors: Linda M. Reis, Elena A. Sorokina, Samuel Thompson, Sanaa Muheisen, Milen Velinov, Carlos Zamora, Arthur S. Aylsworth, Elena V. Semina Tags: Report Source Type: research

Comparing Within- and Between-Family Polygenic Score Prediction
Polygenic scores are a popular tool for prediction of complex traits. However, prediction estimates in samples of unrelated participants can include effects of population stratification, assortative mating, and environmentally mediated parental genetic effects, a form of genotype-environment correlation (rGE). Comparing genome-wide polygenic score (GPS) predictions in unrelated individuals with predictions between siblings in a within-family design is a powerful approach to identify these different sources of prediction. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 11, 2019 Category: Genetics & Stem Cells Authors: Saskia Selzam, Stuart J. Ritchie, Jean-Baptiste Pingault, Chandra A. Reynolds, Paul F. O ’Reilly, Robert Plomin Tags: Article Source Type: research

De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder
POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 11, 2019 Category: Genetics & Stem Cells Authors: Lot Snijders Blok, Tjitske Kleefstra, Hanka Venselaar, Saskia Maas, Hester Y. Kroes, Augusta M.A. Lachmeijer, Koen L.I. van Gassen, Helen V. Firth, Susan Tomkins, Simon Bodek, The DDD Study, Katrin Õunap, Monica H. Wojcik, Christopher Cunniff, Katherine Tags: Report Source Type: research

Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1
Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individu...
Source: The American Journal of Human Genetics - July 11, 2019 Category: Genetics & Stem Cells Authors: Norbert F. Ajeawung, Thi Tuyet Mai Nguyen, Linchao Lu, Thomas J. Kucharski, Justine Rousseau, Sirinart Molidperee, Joshua Atienza, Isabel Gamache, Weidong Jin, Sharon E. Plon, Brendan H. Lee, Jose G. Teodoro, Lisa L. Wang, Philippe M. Campeau Tags: Report Source Type: research

Australian Genomics: A Federated Model for Integrating Genomics into Healthcare
Australian Genomics is a national collaborative research partnership of more than 80 organizations piloting a whole-of-system approach to integrating genomics into healthcare that is based on federation principles. The aim of Australian Genomics is to assess the application of genomic testing in healthcare at the translational interface between research and clinical delivery, with an emphasis on robust evaluation of outcomes. It encompasses two bodies of work: a research program prospectively providing genomic testing through exemplar clinical projects in rare diseases, cancers, and reproductive carrier screening and inter...
Source: The American Journal of Human Genetics - July 3, 2019 Category: Genetics & Stem Cells Authors: Zornitza Stark, Tiffany Boughtwood, Peta Phillips, John Christodoulou, David P. Hansen, Jeffrey Braithwaite, Ainsley J. Newson, Clara L. Gaff, Andrew H. Sinclair, Kathryn N. North Tags: Commentary Source Type: research

David “DJ” Weatherall
Professor Sir David J. Weatherall, affectionately known as DJ, passed away on 8, December 2018, aged 85 years. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 3, 2019 Category: Genetics & Stem Cells Authors: Tim E. Peto, Rosalind M. Harding, Jonathan Flint Tags: Obituary Source Type: research

This Month in The Journal
Genome-wide association studies (GWASs) are moving increasingly toward evaluating signals in a tissue-specific, disease-relevant environment. For example, exploring data in these contexts could provide clarity for disease processes that alter gene regulation in a specific tissue for a given complex trait. However, there are currently limited resources and data to perform this type of analysis. In this issue, Çalışkan et al. develop an approach for annotating and fine-mapping regulatory regions in the liver. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 3, 2019 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Analyzing and Reanalyzing the Genome: Findings from the MedSeq Project
Although genome sequencing is increasingly available in clinical and research settings, many questions remain about the interpretation of sequencing data. In the MedSeq Project, we explored how much effort is required to evaluate and report on more than 4,500 genes reportedly associated with monogenic conditions, as well as pharmacogenomic (PGx) markers, blood antigen serotyping, and polygenic risk scores in 100 individuals (50 with cardiomyopathy and 50 healthy) randomized to the sequencing arm. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 27, 2019 Category: Genetics & Stem Cells Authors: Kalotina Machini, Ozge Ceyhan-Birsoy, Danielle R. Azzariti, Himanshu Sharma, Peter Rossetti, Lisa Mahanta, Laura Hutchinson, Heather McLaughlin, The MedSeq Project, Robert C. Green, Matthew Lebo, Heidi L. Rehm Tags: Article Source Type: research

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases
We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 27, 2019 Category: Genetics & Stem Cells Authors: Yoshiko Murakami, Thi Tuyet Mai Nguyen, Nissan Baratang, Praveen K. Raju, Alexej Knaus, Sian Ellard, Gabriela Jones, Baiba Lace, Justine Rousseau, Norbert Fonya Ajeawung, Atsushi Kamei, Gaku Minase, Manami Akasaka, Nami Araya, Eriko Koshimizu, Jenneke van Tags: Article Source Type: research

Paralog Studies Augment Gene Discovery: DDX and DHX Genes
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 27, 2019 Category: Genetics & Stem Cells Authors: Ingrid Paine, Jennifer E. Posey, Christopher M. Grochowski, Shalini N. Jhangiani, Sarah Rosenheck, Robert Kleyner, Taylor Marmorale, Margaret Yoon, Kai Wang, Reid Robison, Gerarda Cappuccio, Michele Pinelli, Adriano Magli, Zeynep Coban Akdemir, Joannie Hu Tags: Article Source Type: research

Inference of Population Structure from Time-Series Genotype Data
We present DyStruct, a model and inference algorithm for inferring shared ancestry from temporally sampled genotype data. DyStruct explicitly incorporates temporal dynamics by modeling individuals as mixtures of unobserved populations whose allele frequencies drift over time. We develop an efficient inference algorithm for our model using stochastic variational inference. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 27, 2019 Category: Genetics & Stem Cells Authors: Tyler A. Joseph, Itsik Pe ’er Tags: Article Source Type: research

Public Discussion Affects Question Asking at Academic Conferences
Women are under-represented in science, technology, engineering, and mathematics (STEM). Despite the recent emphasis on diversity in STEM, our understanding of what drives differences between women and men scientists remains limited. This, in turn, limits our ability to intervene to level the playing field. To quantify the representation and participation of women and men at academic meetings in human genetics, we developed high-throughput and crowd-sourced approaches focused on question-asking behavior. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 27, 2019 Category: Genetics & Stem Cells Authors: Natalie Telis, Emily C. Glassberg, Jonathan K. Pritchard, Chris Gunter Tags: Article Source Type: research

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. (Source: T...
Source: The American Journal of Human Genetics - June 21, 2019 Category: Genetics & Stem Cells Authors: Davut Pehlivan, Yavuz Bayram, Nilay Gunes, Zeynep Coban Akdemir, Anju Shukla, Tatjana Bierhals, Burcu Tabakci, Yavuz Sahin, Alper Gezdirici, Jawid M. Fatih, Elif Yilmaz Gulec, Gozde Yesil, Jaya Punetha, Zeynep Ocak, Christopher M. Grochowski, Ender Karaca Tags: Article Source Type: research

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders
De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. (Source: The American ...
Source: The American Journal of Human Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Marija Dulovic-Mahlow, Joanne Trinh, Krishna Kumar Kandaswamy, Geir Julius Braathen, Nataliya Di Donato, Elisa Rahikkala, Skadi Beblo, Martin Werber, Victor Krajka, Øyvind L. Busk, Hauke Baumann, Nouriya Abbas Al-Sannaa, Frauke Hinrichs, Rabea Affan, Nir Tags: Report Source Type: research

NCALD Antisense Oligonucleotide Therapy in Addition to Nusinersen further Ameliorates Spinal Muscular Atrophy in Mice
Spinal muscular atrophy (SMA) is a neuromuscular disease causing the most frequent genetic childhood lethality. Recently, nusinersen, an antisense oligonucleotide (ASO) that corrects SMN2 splicing and thereby increases full-length SMN protein, has been approved by the FDA and EMA for SMA therapy. However, the administration of nusinersen in severe and/or post-symptomatic SMA-affected individuals is insufficient to counteract the disease. Therefore, additional SMN-independent therapies are needed to support the function of motoneurons and neuromuscular junctions. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Laura Torres-Benito, Svenja Schneider, Roman Rombo, Karen K. Ling, Vanessa Grysko, Aaradhita Upadhyay, Natalia L. Kononenko, Frank Rigo, C. Frank Bennett, Brunhilde Wirth Tags: Report Source Type: research

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Haloom Rafehi, David J. Szmulewicz, Mark F. Bennett, Nara L.M. Sobreira, Kate Pope, Katherine R. Smith, Greta Gillies, Peter Diakumis, Egor Dolzhenko, Michael A. Eberle, Mar ía García Barcina, David P. Breen, Andrew M. Chancellor, Phillip D. Cremer, Mar Tags: Article Source Type: research

TIGAR: An Improved Bayesian Tool for Transcriptomic Data Imputation Enhances Gene Mapping of Complex Traits
The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Sini Nagpal, Xiaoran Meng, Michael P. Epstein, Lam C. Tsoi, Matthew Patrick, Greg Gibson, Philip L. De Jager, David A. Bennett, Aliza P. Wingo, Thomas S. Wingo, Jingjing Yang Tags: Article Source Type: research

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction
Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 13, 2019 Category: Genetics & Stem Cells Authors: Jianbo Tian, Jiang Chang, Jing Gong, Jiao Lou, Mingpeng Fu, Jiaoyuan Li, Juntao Ke, Ying Zhu, Yajie Gong, Yang Yang, Danyi Zou, Xiating Peng, Nan Yang, Shufang Mei, Xiaoyang Wang, Rong Zhong, Kailin Cai, Xiaoping Miao Tags: Article Source Type: research

Genes for Good: Engaging the Public in Genetics Research via Social Media
The Genes for Good study uses social media to engage a large, diverse participant pool in genetics research and education. Health history and daily tracking surveys are administered through a Facebook application, and participants who complete a minimum number of surveys are mailed a saliva sample kit ( “spit kit”) to collect DNA for genotyping. As of March 2019, we engaged>80,000 individuals, sent spit kits to>32,000 individuals who met minimum participation requirements, and collected>27,000 spit kits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 13, 2019 Category: Genetics & Stem Cells Authors: Katharine Brieger, Gregory J.M. Zajac, Anita Pandit, Johanna R. Foerster, Kevin W. Li, Aubrey C. Annis, Ellen M. Schmidt, Chris P. Clark, Karly McMorrow, Wei Zhou, Jingjing Yang, Alan M. Kwong, Andrew P. Boughton, Jinxi Wu, Chris Scheller, Tanvi Parikh, A Tags: Article Source Type: research

Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver
Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. (Sourc...
Source: The American Journal of Human Genetics - June 13, 2019 Category: Genetics & Stem Cells Authors: Minal Çalışkan, Elisabetta Manduchi, H. Shanker Rao, Julian A. Segert, Marcia Holsbach Beltrame, Marco Trizzino, YoSon Park, Samuel W. Baker, Alessandra Chesi, Matthew E. Johnson, Kenyaita M. Hodge, Michelle E. Leonard, Baoli Loza, Dong Xin, Andrea M. Tags: Article Source Type: research

RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities
We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 13, 2019 Category: Genetics & Stem Cells Authors: Margot A. Cousin, Erin Conboy, Jian-She Wang, Dominic Lenz, Tanya L. Schwab, Monique Williams, Roshini S. Abraham, Sarah Barnett, Mounif El-Youssef, Rondell P. Graham, Luz Helena Gutierrez Sanchez, Linda Hasadsri, Georg F. Hoffmann, Nathan C. Hull, Robert Tags: Article Source Type: research

Third-Party Genetic Interpretation Tools: A Mixed-Methods Study of Consumer Motivation and Behavior
In an effort to meet ethical obligations and/or participant expectations, researchers may consider offering “raw” or uninterpreted genetic data for result return. It is therefore important to understand the motivations, behaviors, and perspectives of individuals who might choose to access raw data before such return becomes routine. In the direct-to-consumer (DTC) context, where raw data are often mad e available to customers, the use of third-party interpretation tools has raised concerns about genotype accuracy, data privacy, reliability of interpretation, and consumption of limited health care resources. (So...
Source: The American Journal of Human Genetics - June 13, 2019 Category: Genetics & Stem Cells Authors: Sarah C. Nelson, Deborah J. Bowen, Stephanie M. Fullerton Tags: Article Source Type: research

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia
(The American Journal of Human Genetics 104, 767 –773; April 4, 2019) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 6, 2019 Category: Genetics & Stem Cells Authors: Mohammad Ali Farazi Fard, Adriana P. Rebelo, Elena Buglo, Hamid Nemati, Hassan Dastsooz, Ina Gehweiler, Selina Reich, Jennifer Reichbauer, Beatriz Quint áns, Andrés Ordóñez-Ugalde, Andrea Cortese, Steve Courel, Lisa Abreu, Eric Powell, Matt C. Danzi, Tags: Correction Source Type: research

This Month in The Journal
Even within tissue-specific databases, there is still a large amount of heterogeneity, possibly due to the various cell types that compose a specific tissue. It is possible that tissue-specific associations could be further refined if these associations could be explored at the level of cell type. However, rather than waiting until cell atlases become more readily available, one might be able to use in silico approaches to deconvolute the cell type composition of a tissue sample and then use this information to reassess associations with a given trait or disease. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 6, 2019 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors ’ Corner Source Type: research

Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia
Motile cilia and sperm flagella share an evolutionarily conserved axonemal structure. Their structural and/or functional defects are associated with primary ciliary dyskinesia (PCD), a genetic disease characterized by chronic respiratory-tract infections and in which most males are infertile due to asthenozoospermia. Among the well-characterized axonemal protein complexes, the outer dynein arms (ODAs), through ATPase activity of their heavy chains (HCs), play a major role for cilia and flagella beating. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 6, 2019 Category: Genetics & Stem Cells Authors: Marjorie Whitfield, Lucie Thomas, Emilie Bequignon, Alain Schmitt, Laurence Stouvenel, Guy Montantin, Sylvie Tissier, Philippe Duquesnoy, Bruno Copin, Sandra Chantot, Florence Dastot, Catherine Faucon, Anne Laure Barbotin, Anne Loyens, Jean-Pierre Siffroi Tags: Report Source Type: research