Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Nicole J. Lake, Bryn D. Webb, David A. Stroud, Tara R. Richman, Benedetta Ruzzenente, Alison G. Compton, Hayley S. Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Bodaert, Zahra Assouline, Mingma D. Sherpa, Eric E. Schadt, Sander M. Tags: Article Source Type: research

Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction
Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Miroslav P. Milev, Megan E. Grout, Djenann Saint-Dic, Yong-Han Hank Cheng, Ian A. Glass, Christopher J. Hale, David S. Hanna, Michael O. Dorschner, Keshika Prematilake, Avraham Shaag, Orly Elpeleg, Michael Sacher, Dan Doherty, Simon Edvardson Tags: Report Source Type: research

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage
Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Joshua A. Betts, Mahdi Moradi Marjaneh, Fares Al-Ejeh, Yi Chieh Lim, Wei Shi, Haran Sivakumaran, Romain Trop ée, Ann-Marie Patch, Michael B. Clark, Nenad Bartonicek, Adrian P. Wiegmans, Kristine M. Hillman, Susanne Kaufmann, Amanda L. Bain, Brian S. Glos Tags: Article Source Type: research

This Month in The Journal
Years of linkage and sequencing studies have demonstrated that the majority of mutations underlying Mendelian disorders reside in the coding region. But many families lack a genetic diagnosis, leading to the suggestion that regulatory regions could be a source of additional pathogenic variation. However, there are only a few examples of monogenic disorders caused by mutations outside of the exons, and the contribution of noncoding regions to Mendelian disease remains unclear. Now, Gasperini et  al. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

This Month in Genetics
In human genetics, we tend to fixate on the negative effects of genetic variation. After all, how many stories about the “breast cancer gene” have you read? There is much more nuance to genetic variation, though, and genes are not all “bad.” Such is the case with GDF5, which encodes a growth differentiation factor. Although one could think of it as the gene for certain types of short-limbed dwarfism because th ese are the result of rare mutations in the gene, more common GDF5 variation can actually make you taller. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

Continuity and Admixture in the Last Five Millennia of Levantine History from Ancient Canaanite and Present-Day Lebanese Genome Sequences
In this study, we sequenced five whole genomes from ∼3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 27, 2017 Category: Genetics & Stem Cells Authors: Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Micha ł Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas K Tags: Report Source Type: research

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 27, 2017 Category: Genetics & Stem Cells Authors: Despoina Manousaki, Tom Dudding, Simon Haworth, Yi-Hsiang Hsu, Ching-Ti Liu, Carolina Medina-G ómez, Trudy Voortman, Nathalie van der Velde, Håkan Melhus, Cassianne Robinson-Cohen, Diana L. Cousminer, Maria Nethander, Liesbeth Vandenput, Raymond Noordam Tags: Article Source Type: research

Leveraging Multi-Ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations
An essential component of precision medicine is the ability to predict an individual ’s risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set o f risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 27, 2017 Category: Genetics & Stem Cells Authors: Marc A. Coram, Huaying Fang, Sophie I. Candille, Themistocles L. Assimes, Hua Tang Tags: Article Source Type: research

Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy
Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism ( α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), l ipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy c...
Source: The American Journal of Human Genetics - July 27, 2017 Category: Genetics & Stem Cells Authors: Florence Habarou, Yamina Hamel, Tobias B. Haack, Ren é G. Feichtinger, Elise Lebigot, Iris Marquardt, Kanetee Busiah, Cécile Laroche, Marine Madrange, Coraline Grisel, Clément Pontoizeau, Monika Eisermann, Audrey Boutron, Dominique Chrétien, Bernadett Tags: Report Source Type: research

Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 20, 2017 Category: Genetics & Stem Cells Authors: Cinthya J. Zepeda-Mendoza, Jonas Ibn-Salem, Tammy Kammin, David J. Harris, Debra Rita, Karen W. Gripp, Jennifer J. MacKenzie, Andrea Gropman, Brett Graham, Ranad Shaheen, Fowzan S. Alkuraya, Campbell K. Brasington, Edward J. Spence, Diane Masser-Frye, Lyn Tags: Article Source Type: research

CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions
The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ( “ScanDel”). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 13, 2017 Category: Genetics & Stem Cells Authors: Molly Gasperini, Gregory M. Findlay, Aaron McKenna, Jennifer H. Milbank, Choli Lee, Melissa D. Zhang, Darren A. Cusanovich, Jay Shendure Tags: Article Source Type: research

Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease
Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Parisa Shooshtari, Hailiang Huang, Chris Cotsapas Tags: Article Source Type: research

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Cara M. Skraban, Constance F. Wells, Preetha Markose, Megan T. Cho, Addie I. Nesbitt, P.Y. Billie Au, Amber Begtrup, John A. Bernat, Lynne M. Bird, Kajia Cao, Arjan P.M. de Brouwer, Elizabeth H. Denenberg, Ganka Douglas, Kristin M. Gibson, Katheryn Grand, Tags: Report Source Type: research

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression
(The American Journal of Human Genetics 100, 885 –894; June 1, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Mads Engel Hauberg, Wen Zhang, Claudia Giambartolomei, Oscar Franz én, David L. Morris, Timothy J. Vyse, Arno Ruusalepp, CommonMind Consortium, Pamela Sklar, Eric E. Schadt, Johan L.M. Björkegren, Panos Roussos Tags: Correction Source Type: research

10 Years of GWAS Discovery: Biology, Function, and Translation
Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Peter M. Visscher, Naomi R. Wray, Qian Zhang, Pamela Sklar, Mark I. McCarthy, Matthew A. Brown, Jian Yang Tags: Review Source Type: research

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis
Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3 –p22.3, 5q13–q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Yavuz Bayram, Janson J. White, Nursel Elcioglu, Megan T. Cho, Neda Zadeh, Asuman Gedikbasi, Sukru Palanduz, Sukru Ozturk, Kivanc Cefle, Ozgur Kasapcopur, Zeynep Coban Akdemir, Davut Pehlivan, Amber Begtrup, Claudia M.B. Carvalho, Ingrid Sophie Paine, Ali Tags: Report Source Type: research

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia
Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Ana I. Seixas, Joana R. Loureiro, Cristina Costa, Andr és Ordóñez-Ugalde, Hugo Marcelino, Cláudia L. Oliveira, José L. Loureiro, Ashutosh Dhingra, Eva Brandão, Vitor T. Cruz, Angela Timóteo, Beatriz Quintáns, Guy A. Rouleau, Patrizia Rizzu, Ángel Tags: Article Source Type: research

This Month in Genetics
It ’s not the first time it’s happened, but rare variation in individuals with exceptional lipid profiles has again pointed to a new target for intervention in cardiovascular disease. Exome sequencing in more than one study has revealed rare, loss-of-function variation in ANGPTL3—which encodes an endogenous lipoprotein lipase inhibitor—in individuals with very low levels of triglycerides and low-density lipoprotein (LDL) cholesterol. Expanding the implications of this finding, Dewey et al. report that heterozygous carriers of these rare variants also have lower levels than non-carrier...
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

This Month in The Journal
Joubert syndrome (JS) is a ciliopathy characterized by hypotonia, ataxia, and a “molar tooth sign” on MRI, and it can also involve cognitive defects. This genetically heterogeneous disorder is caused by mutations in more than three dozen genes that encode proteins required for cilia formation or function. In this issue, Van de Weghe et al. identify ARMC9 mutations in eigh t JS-affected families in whom mutations in previously associated genes had already been ruled. The families were ascertained through different mechanisms, but the combined cohort data suggest that ARMC9 mutations might explain the g...
Source: The American Journal of Human Genetics - July 6, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression
A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next -generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) block...
Source: The American Journal of Human Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Diyu Chen, Yangjin Zuo, Xinhua Zhang, Yuhua Ye, Xiuqin Bao, Haiyan Huang, Wanicha Tepakhan, Lijuan Wang, Junyi Ju, Guangfu Chen, Mincui Zheng, Dun Liu, Shuodan Huang, Lu Zong, Changgang Li, Yajun Chen, Chenguang Zheng, Lihong Shi, Quan Zhao, Qiang Wu, Sup Tags: Report Source Type: research

Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life
Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). (Source: The Ameri...
Source: The American Journal of Human Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Rocio Acuna-Hidalgo, Hilal Sengul, Marloes Steehouwer, Maartje van de Vorst, Sita H. Vermeulen, Lambertus A.L.M. Kiemeney, Joris A. Veltman, Christian Gilissen, Alexander Hoischen Tags: Article Source Type: research

A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases
We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian ...
Source: The American Journal of Human Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Daniel Greene, NIHR BioResource, Sylvia Richardson, Ernest Turro Tags: Article Source Type: research

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy
KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Anna Lehman, Samrat Thouta, Grazia M.S. Mancini, Sakkubai Naidu, Marjon van Slegtenhorst, Kirsty McWalter, Richard Person, Jill Mwenifumbo, Ramona Salvarinova, CAUSES Study, EPGEN Study, Ilaria Guella, Marna B. McKenzie, Anita Datta, Mary B. Connolly, Som Tags: Article Source Type: research

SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant Association Studies using Whole-Genome and Exome Sequence Data
Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed...
Source: The American Journal of Human Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Di Zhang, Linhai Zhao, Biao Li, Zongxiao He, Gao T. Wang, Dajiang J. Liu, Suzanne M. Leal Tags: Report Source Type: research

Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the “molar tooth sign” on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of fami lies the genetic cause remains unknown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 15, 2017 Category: Genetics & Stem Cells Authors: Julie C. Van De Weghe, Tamara D.S. Rusterholz, Brooke Latour, Megan E. Grout, Kimberly A. Aldinger, Ranad Shaheen, Jennifer C. Dempsey, Sateesh Maddirevula, Yong-Han H. Cheng, Ian G. Phelps, Matthias Gesemann, Himanshu Goel, Ohad S. Birk, Talal Alanzi, Ri Tags: Article Source Type: research

Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that  other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 8, 2017 Category: Genetics & Stem Cells Authors: Danny Halim, Erwin Brosens, Fran çoise Muller, Michael F. Wangler, Arthur L. Beaudet, James R. Lupski, Zeynep H. Coban Akdemir, Michael Doukas, Hans J. Stoop, Bianca M. de Graaf, Rutger W.W. Brouwer, Wilfred F.J. van Ijcken, Jean-François Oury, Jonathan Tags: Report Source Type: research

A Fast and Accurate Algorithm to Test for Binary Phenotypes and Its Application to PheWAS
The availability of electronic health record (EHR)-based phenotypes allows for genome-wide association analyses in thousands of traits and has great potential to enable identification of genetic variants associated with clinical phenotypes. We can interpret the phenome-wide association study (PheWAS) result for a single genetic variant by observing its association across a landscape of phenotypes. Because a PheWAS can test thousands of binary phenotypes, and most of them have unbalanced or often extremely unbalanced case-control ratios (1:10 or 1:600, respectively), existing methods cannot provide an accurate and scalable ...
Source: The American Journal of Human Genetics - June 8, 2017 Category: Genetics & Stem Cells Authors: Rounak Dey, Ellen M. Schmidt, Goncalo R. Abecasis, Seunggeun Lee Tags: Article Source Type: research

Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin- β-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Evangelia S. Panagiotou, Carla Sanjurjo Soriano, James A. Poulter, Emma C. Lord, Denisa Dzulova, Hiroyuki Kondo, Atsushi Hiyoshi, Brian Hon-Yin Chung, Yoyo Wing-Yiu Chu, Connie H.Y. Lai, Mark E. Tafoya, Dyah Karjosukarso, Rob W.J. Collin, Joanne Topping, Tags: Report Source Type: research

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits
(The American Journal of Human Genetics 100, 571 –580; April 6, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Chen Yao, Roby Joehanes, Andrew D. Johnson, Tianxiao Huan, Chunyu Liu, Jane E. Freedman, Peter J. Munson, David E. Hill, Marc Vidal, Daniel Levy Tags: Correction Source Type: research

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma
The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Lynn M. Boyden, Nicholas G. Vincent, Jing Zhou, Ronghua Hu, Brittany G. Craiglow, Susan J. Bayliss, Ilana S. Rosman, Anne W. Lucky, Luis A. Diaz, Lowell A. Goldsmith, Amy S. Paller, Richard P. Lifton, Susan J. Baserga, Keith A. Choate Tags: Report Source Type: research

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease
Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Yi-An Ko, Huiguang Yi, Chengxiang Qiu, Shizheng Huang, Jihwan Park, Nora Ledo, Anna K öttgen, Hongzhe Li, Daniel J. Rader, Michael A. Pack, Christopher D. Brown, Katalin Susztak Tags: Article Source Type: research

This Month in Genetics
Even with exome and whole-genome sequencing, diagnoses can be made in only about one-quarter of individuals presumed to have a Mendelian disorder. Not satisfied with this success rate, Cummings et  al. made use of the fact that many people with muscular disorders have muscle biopsies as part of their diagnostic workup and used these samples as sources of RNA for transcript analysis in muscle. They compared RNA sequencing (RNA-seq) of the biopsies with a large control dataset to seek DNA vari ants that affect RNA splicing or the relative abundance of the two alleles. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction
Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1  acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and vari ous congenital malformations. Our combined clinical and molecular data define “YY1 syndrome” as a haploinsufficiency syndrome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Michele Gabriele, Anneke T. Vulto-van Silfhout, Pierre-Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J. Pedurup Tags: Article Source Type: research

Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans
Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member  1 (SULT2B1), showing their causative association with ARCI. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Lisa Heinz, Gwang-Jin Kim, Slaheddine Marrakchi, Julie Christiansen, Hamida Turki, Marc-Alexander Rauschendorf, Mark Lathrop, Ingrid Hausser, Andreas D. Zimmer, Judith Fischer Tags: Article Source Type: research

This Month in The Journal
The pace of research aiming to identify disease-associated human alleles has increased markedly since the introduction of next-generation sequencing. However, work to demonstrate pathogenicity remains laborious, and many variants remain classified as being of unknown significance. In addition to experiments aimed at directly testing discrete variants, model systems have been used for generating a wealth of information about genes whose homologs are implicated in human disease. However, accessing all the relevant information can be time intensive and cumbersome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
We report seven individuals with an early-onset spastic-ataxia phenotype. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 1, 2017 Category: Genetics & Stem Cells Authors: Viorica Chelban, Nisha Patel, Jana Vandrovcova, M. Natalia Zanetti, David S. Lynch, Mina Ryten, Juan A. Bot ía, Oscar Bello, Eloise Tribollet, Stephanie Efthymiou, Indran Davagnanam, SYNAPSE Study Group, Fahad A. Bashiri, Nicholas W. Wood, James E. Rothm Tags: Report Source Type: research

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella
Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a m...
Source: The American Journal of Human Genetics - May 25, 2017 Category: Genetics & Stem Cells Authors: Shuyan Tang, Xiong Wang, Weiyu Li, Xiaoyu Yang, Zheng Li, Wangjie Liu, Caihua Li, Zijue Zhu, Lingxiang Wang, Jiaxiong Wang, Ling Zhang, Xiaoling Sun, Erlei Zhi, Hongyan Wang, Hong Li, Li Jin, Yang Luo, Jian Wang, Shenmin Yang, Feng Zhang Tags: Article Source Type: research

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits
We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 25, 2017 Category: Genetics & Stem Cells Authors: Ioanna Tachmazidou, D ániel Süveges, Josine L. Min, Graham R.S. Ritchie, Julia Steinberg, Klaudia Walter, Valentina Iotchkova, Jeremy Schwartzentruber, Jie Huang, Yasin Memari, Shane McCarthy, Andrew A. Crawford, Cristina Bombieri, Massimiliano Cocca, A Tags: Article Source Type: research

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource
With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. (Source...
Source: The American Journal of Human Genetics - May 25, 2017 Category: Genetics & Stem Cells Authors: Natasha T. Strande, Erin Rooney Riggs, Adam H. Buchanan, Ozge Ceyhan-Birsoy, Marina DiStefano, Selina S. Dwight, Jenny Goldstein, Rajarshi Ghosh, Bryce A. Seifert, Tam P. Sneddon, Matt W. Wright, Laura V. Milko, J. Michael Cherry, Monica A. Giovanni, Mich Tags: Article Source Type: research

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression
Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate (Source: The Americ...
Source: The American Journal of Human Genetics - May 25, 2017 Category: Genetics & Stem Cells Authors: Mads Engel Hauberg, Wen Zhang, Claudia Giambartolomei, Oscar Franz én, David L. Morris, Timothy J. Vyse, Arno Ruusalepp, CommonMind Consortium, Pamela Sklar, Eric E. Schadt, Johan L.M. Björkegren, Panos Roussos Tags: Article Source Type: research

Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci
Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 18, 2017 Category: Genetics & Stem Cells Authors: Eilis Hannon, Mike Weedon, Nicholas Bray, Michael O ’Donovan, Jonathan Mill Tags: Report Source Type: research

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome
One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 11, 2017 Category: Genetics & Stem Cells Authors: Julia Wang, Rami Al-Ouran, Yanhui Hu, Seon-Young Kim, Ying-Wooi Wan, Michael F. Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, Aram Comjean, Stephanie E. Mohr, UDN, Norbert Perrimon, Zhandong Liu, Hugo J. Bellen Tags: Article Source Type: research

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability
To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a produ ct that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and i...
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Katrina Tatton-Brown, Chey Loveday, Shawn Yost, Matthew Clarke, Emma Ramsay, Anna Zachariou, Anna Elliott, Harriet Wylie, Anna Ardissone, Olaf Rittinger, Fiona Stewart, I. Karen Temple, Trevor Cole, Childhood Overgrowth Collaboration, Shazia Mahamdallie, Tags: Article Source Type: research

Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites
We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cy...
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Melissa Lee, Patrick Roos, Neeraj Sharma, Melis Atalar, Taylor A. Evans, Matthew J. Pellicore, Emily Davis, Anh-Thu N. Lam, Susan E. Stanley, Sara E. Khalil, George M. Solomon, Doug Walker, Karen S. Raraigh, Briana Vecchio-Pagan, Mary Armanios, Garry R. C Tags: Article Source Type: research

Inferring Human Demographic Histories of Non-African Populations from Patterns of Allele Sharing
Recent human-genetics studies have come to different conclusions regarding how and when modern humans spread out of Africa and into the rest of the world. I present here a simple parsimony-based analysis that suggests that East Asians and Melanesians are sister groups, and I discuss what implications this has for recent claims made about the demographic histories of non-African populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Jeffrey D. Wall Tags: Article Source Type: research

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of ...
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Kym M. Boycott, Ana Rath, Jessica X. Chong, Taila Hartley, Fowzan S. Alkuraya, Gareth Baynam, Anthony J. Brookes, Michael Brudno, Angel Carracedo, Johan T. den Dunnen, Stephanie O.M. Dyke, Xavier Estivill, Jack Goldblatt, Catherine Gonthier, Stephen C. Gr Tags: Commentary Source Type: research

CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions
Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein  7 (CHD7LOF) and lysine (K) methyltransferase 2D (KMT2DLOF), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA me thylation (DNAm) alterations downstream of the mutations in these genes woul...
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Darci T. Butcher, Cheryl Cytrynbaum, Andrei L. Turinsky, Michelle T. Siu, Michal Inbar-Feigenberg, Roberto Mendoza-Londono, David Chitayat, Susan Walker, Jerry Machado, Oana Caluseriu, Lucie Dupuis, Daria Grafodatskaya, William Reardon, Brigitte Gilbert-D Tags: Article Source Type: research

Widespread Allelic Heterogeneity in Complex Traits
Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH  and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Farhad Hormozdiari, Anthony Zhu, Gleb Kichaev, Chelsea J.-T. Ju, Ayellet V. Segr è, Jong Wha J. Joo, Hyejung Won, Sriram Sankararaman, Bogdan Pasaniuc, Sagiv Shifman, Eleazar Eskin Tags: Article Source Type: research

This Month in Genetics
Chromosome recombination is a critical process for ensuring proper chromosome segregation. It provides the necessary tension at the kinetochore to orient the homologous chromosomes before the first meiotic division and keeps them together until it ’s time for the homologs to separate. Although as far as we know the basic process of recombination is the same in males and females, differences have been documented in terms of the number and distribution of crossover events in sperm and oocytes. In fact, although the number of crossover initiat ions, as marked by MLH1 foci, is higher in female germ cells, the frequency o...
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans
Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations. Replicated T2D locations were tested for evidence of being regulatory hotspots using adipose expression. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Winston Lau, Toby Andrew, Nikolas Maniatis Tags: Article Source Type: research