Mutations Preventing Regulated Exon Skipping in Cause Osteofibrous Dysplasia
The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Mary J. Gray, Peter Kannu, Swarkar Sharma, Christine Neyt, Dongping Zhang, Nandina Paria, Philip B. Daniel, Heather Whetstone, Hans-Georg Sprenger, Philipp Hammerschmidt, Angela Weng, Lucie Dupuis, Rebekah Jobling, Roberto Mendoza-Londono, Michael Dray, Tags: Article Source Type: research

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene
Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), af...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Kym M. Boycott, Chandree L. Beaulieu, Kristin D. Kernohan, Ola H. Gebril, Aziz Mhanni, Albert E. Chudley, David Redl, Wen Qin, Sarah Hampson, Sébastien Küry, Martine Tetreault, Erik G. Puffenberger, James N. Scott, Stéphane Bezieau, André Reis, Tags: Report Source Type: research

SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation
SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Julien H. Park, Max Hogrebe, Marianne Grüneberg, Ingrid DuChesne, Ava L. von der Heiden, Janine Reunert, Karl P. Schlingmann, Kym M. Boycott, Chandree L. Beaulieu, Aziz A. Mhanni, A. Micheil Innes, Konstanze Hörtnagel, Saskia Biskup, Eva M. Gl Tags: Report Source Type: research

Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations
We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleo...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Jason A. O’Rawe, Yiyang Wu, Max J. Dörfel, Alan F. Rope, P.Y. Billie Au, Jillian S. Parboosingh, Sungjin Moon, Maria Kousi, Konstantina Kosma, Christopher S. Smith, Maria Tzetis, Jane L. Schuette, Robert B. Hufnagel, Carlos E. Prada, Francisco Tags: Report Source Type: research

De Novo Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome
Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Lindsay C. Burrage, Wu-Lin Charng, Mohammad K. Eldomery, Jason R. Willer, Erica E. Davis, Dorien Lugtenberg, Wenmiao Zhu, Magalie S. Leduc, Zeynep C. Akdemir, Mahshid Azamian, Gladys Zapata, Patricia P. Hernandez, Jeroen Schoots, Sonja A. de Munn Tags: Report Source Type: research

This Month in
Genome-wide association studies (GWASs) have produced vast numbers of SNPs associated with various traits; however, the nature of many of these signals remains unclear. Determining the true functional variants underlying the signal and the consequences of variation at these sites requires experimental validation of each of these GWAS loci. In this issue, Roman et al. fine mapped a region near GALNT2, a gene whose protein product is involved in high-density lipoprotein cholesterol (HDL-C) metabolism and associated with blood lipid and cholesterol levels. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors’ Corner Source Type: research

This Month in Genetics
Collecting information on consanguinity is one of the core concepts of documenting a family’s genetic history. When it is present, suspicion increases for autosomal-recessive disorders because of increased allele sharing. Researchers from Ambry Genetics recently assessed whether this theory bears out. They combed through their first 500 exome samples to identify cases of known consanguinity and then compared the results in these consanguineous cases to the results from the rest of the samples. The diagnostic rate from the exomes was similar in the consanguineous group, but unexpectedly, nearly 40% of the diagnostic f...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors’ Corner Source Type: research

Somatic Activating Mutations Cause Venous Malformation
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for>92% of individuals who carry mutations. (Source: The Ameri...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Nisha Limaye, Jaakko Kangas, Antonella Mendola, Catherine Godfraind, Matthieu J. Schlögel, Raphael Helaers, Lauri Eklund, Laurence M. Boon, Miikka Vikkula Tags: Report Source Type: research

Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in , Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain
The neuromuscular junction (NMJ) consists of a tripartite synapse with a presynaptic nerve terminal, Schwann cells that ensheathe the terminal bouton, and a highly specialized postsynaptic membrane. Synaptic structural integrity is crucial for efficient signal transmission. Congenital myasthenic syndromes (CMSs) are a heterogeneous group of inherited disorders that result from impaired neuromuscular transmission, caused by mutations in genes encoding proteins that are involved in synaptic transmission and in forming and maintaining the structural integrity of NMJs. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 25, 2015 Category: Genetics & Stem Cells Authors: Clare V. Logan, Judith Cossins, Pedro M. Rodríguez Cruz, David A. Parry, Susan Maxwell, Pilar Martínez-Martínez, Joey Riepsaame, Zakia A. Abdelhamed, Alice V.R. Lake, Maria Moran, Stephanie Robb, Gabriel Chow, Caroline Sewry, Philip M. Hopkins, Tags: Report Source Type: research

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture
Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected contr...
Source: The American Journal of Human Genetics - November 25, 2015 Category: Genetics & Stem Cells Authors: Philip E. Stuart, Rajan P. Nair, Lam C. Tsoi, Trilokraj Tejasvi, Sayantan Das, Hyun Min Kang, Eva Ellinghaus, Vinod Chandran, Kristina Callis-Duffin, Robert Ike, Yanming Li, Xiaoquan Wen, Charlotta Enerbäck, Johann E. Gudjonsson, Sulev Kõks, Külli Tags: Article Source Type: research

Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans
Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exo...
Source: The American Journal of Human Genetics - November 19, 2015 Category: Genetics & Stem Cells Authors: Hanan Shamseldin, Anas M. Alazami, Melanie Manning, Amal Hashem, Oana Caluseiu, Brahim Tabarki, Edward Esplin, Susan Schelley, A. Micheil Innes, Jillian S. Parboosingh, Ryan Lamont, Care4Rare Canada Consortium, Jacek Majewski, Francois P. Bernier, Fow Tags: Report Source Type: research

Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome
We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF
Source: The American Journal of Human Genetics - November 19, 2015 Category: Genetics & Stem Cells Authors: Tingwei Guo, Jonathan H. Chung, Tao Wang, Donna M. McDonald-McGinn, Wendy R. Kates, Wanda Hawuła, Karlene Coleman, Elaine Zackai, Beverly S. Emanuel, Bernice E. Morrow Tags: Report Source Type: research

Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates
We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 12, 2015 Category: Genetics & Stem Cells Authors: Pier Francesco Palamara, Laurent C. Francioli, Peter R. Wilton, Giulio Genovese, Alexander Gusev, Hilary K. Finucane, Sriram Sankararaman, Genome of the Netherlands Consortium, Shamil R. Sunyaev, Paul I.W. de Bakker, John Wakeley, Itsik Pe’er, Al Tags: Article Source Type: research

Mutations in , Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia
Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna. A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT. However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT. In the current study, we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with R...
Source: The American Journal of Human Genetics - November 12, 2015 Category: Genetics & Stem Cells Authors: Tetsuya Niihori, Meri Ouchi-Uchiyama, Yoji Sasahara, Takashi Kaneko, Yoshiko Hashii, Masahiro Irie, Atsushi Sato, Yuka Saito-Nanjo, Ryo Funayama, Takeshi Nagashima, Shin-ichi Inoue, Keiko Nakayama, Keiichi Ozono, Shigeo Kure, Yoichi Matsubara, Masue Imaiz Tags: Report Source Type: research

Disruptive Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia
Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 12, 2015 Category: Genetics & Stem Cells Authors: Wolfgang M. Schmidt, S. Lane Rutledge, Rebecca Schüle, Benjamin Mayerhofer, Stephan Züchner, Eugen Boltshauser, Reginald E. Bittner Tags: Report Source Type: research

Two-Variance-Component Model Improves Genetic Prediction in Family Datasets
Genetic prediction based on either identity by state (IBS) sharing or pedigree information has been investigated extensively with best linear unbiased prediction (BLUP) methods. Such methods were pioneered in plant and animal-breeding literature and have since been applied to predict human traits, with the aim of eventual clinical utility. However, methods to combine IBS sharing and pedigree information for genetic prediction in humans have not been explored. We introduce a two-variance-component model for genetic prediction: one component for IBS sharing and one for approximate pedigree structure, both estimated with gene...
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: George Tucker, Po-Ru Loh, Iona M. MacLeod, Ben J. Hayes, Michael E. Goddard, Bonnie Berger, Alkes L. Price Tags: Article Source Type: research

Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The - Contiguous Gene Duplication Syndrome
The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct l...
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Bo Yuan, Tamar Harel, Shen Gu, Pengfei Liu, Lydie Burglen, Sandra Chantot-Bastaraud, Violet Gelowani, Christine R. Beck, Claudia M.B. Carvalho, Sau Wai Cheung, Andrew Coe, Valérie Malan, Arnold Munnich, Pilar L. Magoulas, Lorraine Potocki, James R. Tags: Article Source Type: research

Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models
In order to further illuminate the potential role of dominant genetic variation in the “missing heritability” debate, we investigated the additive (narrow-sense heritability, h2) and dominant (δ2) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of δ2 were evident for 14 traits in twin models (average δ2twin = 0.25, range 0.14–0.49), two of which a...
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Xu Chen, Ralf Kuja-Halkola, Iffat Rahman, Johannes Arpegård, Alexander Viktorin, Robert Karlsson, Sara Hägg, Per Svensson, Nancy L. Pedersen, Patrik K.E. Magnusson Tags: Article Source Type: research

This Month in Genetics
Much of what we know about the use of genetic testing for inherited susceptibility to breast and ovarian cancer comes from research studies performed at academic medical centers. To get a broader look at the experience of women who seek this testing, the ABOUT (American BRCA Outcomes and Utilization of Testing) study recruited women via requests for insurance coverage for BRCA testing, thereby ensuring that tests ordered by a variety of healthcare professionals in different settings were represented in the sample. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors’ Corner Source Type: research

Association between Rare Variants in , a Component of Intracellular Trafficking, and Persistent Stuttering
Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. (Source: The Ame...
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: M. Hashim Raza, Rafael Mattera, Robert Morell, Eduardo Sainz, Rachel Rahn, Joanne Gutierrez, Emily Paris, Jessica Root, Beth Solomon, Carmen Brewer, M. Asim Raza Basra, Shaheen Khan, Sheikh Riazuddin, Allen Braun, Juan S. Bonifacino, Dennis Drayna Tags: Article Source Type: research

This Month in
In an effort to promote the sharing of genomic data, the human genetics community has recently established a series of beacons, or web-based tools that are able to provide any interested person with information regarding the presence of particular alleles in a given cohort. Although such beacons are safe from re-identification efforts that rely on allele-frequency data, many beacons contain genomic data gathered from a limited number of individuals, some for only for a particular disease or disorder. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors’ Corner Source Type: research

Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma
(The American Journal of Human Genetics 96, 597–611; April 2, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Ling Zhang, Yong Zhou, Caixia Cheng, Heyang Cui, Le Cheng, Pengzhou Kong, Jiaqian Wang, Yin Li, Wenliang Chen, Bin Song, Fang Wang, Zhiwu Jia, Lin Li, Yaoping Li, Bin Yang, Jing Liu, Ruyi Shi, Yanghui Bi, Yanyan Zhang, Juan Wang, Zhenxiang Zhao, Xiaoling Tags: Erratum Source Type: research

Recessive Mutations in Cause Isolated and Syndromic Optic Neuropathies
(The American Journal of Human Genetics 97, 754–760; November 5, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 5, 2015 Category: Genetics & Stem Cells Authors: Claire Angebault, Pierre-Olivier Guichet, Yasmina Talmat-Amar, Majida Charif, Sylvie Gerber, Lucas Fares-Taie, Naig Gueguen, François Halloy, David Moore, Patrizia Amati-Bonneau, Gael Manes, Maxime Hebrard, Béatrice Bocquet, Mélanie Quiles, Camille Pir Tags: Erratum Source Type: research

Privacy Risks from Genomic Data-Sharing Beacons
The human genetics community needs robust protocols that enable secure sharing of genomic data from participants in genetic research. Beacons are web servers that answer allele-presence queries—such as “Do you have a genome that has a specific nucleotide (e.g., A) at a specific genomic position (e.g., position 11,272 on chromosome 1)?”—with either “yes” or “no.” Here, we show that individuals in a beacon are susceptible to re-identification even if the only data shared include presence or absence information about alleles in a beacon. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 29, 2015 Category: Genetics & Stem Cells Authors: Suyash S. Shringarpure, Carlos D. Bustamante Tags: Article Source Type: research

Allelic Mutations of , Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2
Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. (Source:...
Source: The American Journal of Human Genetics - October 29, 2015 Category: Genetics & Stem Cells Authors: Celia Zazo Seco, Luciana Serrão de Castro, Josephine W. van Nierop, Matías Morín, Shalini Jhangiani, Eva J.J. Verver, Margit Schraders, Nadine Maiwald, Mieke Wesdorp, Hanka Venselaar, Liesbeth Spruijt, Jaap Oostrik, Jeroen Schoots, Baylor-Hopkins Tags: Article Source Type: research

Intra-mitochondrial Methylation Deficiency Due to Mutations in
We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 29, 2015 Category: Genetics & Stem Cells Authors: Yoshihito Kishita, Aleksandra Pajak, Nikhita Ajit Bolar, Carlo M.T. Marobbio, Camilla Maffezzini, Daniela V. Miniero, Magnus Monné, Masakazu Kohda, Henrik Stranneheim, Kei Murayama, Karin Naess, Nicole Lesko, Helene Bruhn, Arnaud Mourier, Rolf Wibom, Tags: Report Source Type: research

Germline Heterozygous Variants in Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer
Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ∼50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. (Source: The American Jo...
Source: The American Journal of Human Genetics - October 29, 2015 Category: Genetics & Stem Cells Authors: Lamis Yehia, Farshad Niazi, Ying Ni, Joanne Ngeow, Madhav Sankunny, Zhigang Liu, Wei Wei, Jessica L. Mester, Ruth A. Keri, Bin Zhang, Charis Eng Tags: Article Source Type: research

Recessive Mutations in Cause Isolated and Syndromic Optic Neuropathies
Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory comple...
Source: The American Journal of Human Genetics - October 22, 2015 Category: Genetics & Stem Cells Authors: Claire Angebault, Pierre-Olivier Guichet, Yasmina Talmat-Amar, Majida Charif, Sylvie Gerber, Lucas Fares-Taie, Naig Gueguen, François Halloy, David Moore, Patrizia Amati-Bonneau, Gael Manes, Maxime Hebrard, Béatrice Bocquet, Mélanie Quiles, Camille Pir Tags: Report Source Type: research

Joubert Syndrome in French Canadians and Identification of Mutations in
Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except...
Source: The American Journal of Human Genetics - October 15, 2015 Category: Genetics & Stem Cells Authors: Myriam Srour, Fadi F. Hamdan, Dianalee McKnight, Erica Davis, Hanna Mandel, Jeremy Schwartzentruber, Brissa Martin, Lysanne Patry, Christina Nassif, Alexandre Dionne-Laporte, Luis H. Ospina, Emmanuelle Lemyre, Christine Massicotte, Rachel Laframboise, B Tags: Report Source Type: research

A Recurrent Mutation in Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia
Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 8, 2015 Category: Genetics & Stem Cells Authors: Marie Coutelier, Iulia Blesneac, Arnaud Monteil, Marie-Lorraine Monin, Kunie Ando, Emeline Mundwiller, Alfredo Brusco, Isabelle Le Ber, Mathieu Anheim, Anna Castrioto, Charles Duyckaerts, Alexis Brice, Alexandra Durr, Philippe Lory, Giovanni Stevanin Tags: Report Source Type: research

Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses
The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable ...
Source: The American Journal of Human Genetics - October 8, 2015 Category: Genetics & Stem Cells Authors: Christian Hammer, Martin Begemann, Paul J. McLaren, István Bartha, Angelika Michel, Beate Klose, Corinna Schmitt, Tim Waterboer, Michael Pawlita, Thomas F. Schulz, Hannelore Ehrenreich, Jacques Fellay Tags: Report Source Type: research

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Tags: Article Source Type: research

Mary Lyon: A Tribute
Mary Lyon passed away on Christmas Day, 2014, at the age of 89. Best known for the X-chromosome-inactivation hypothesis, Mary Lyon was a pioneering geneticist whose findings and syntheses have left a lasting imprint on our understanding of mammalian development and disease (Figure 1). She was the recipient of the 1986 William Allan Award,1 the most prestigious prize given by the American Society of Human Genetics. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Sundeep Kalantry, Jacob L. Mueller Tags: Obituary Source Type: research

This Month in Genetics
Huntington disease is a common example used for initiating discussion about presymptomatic genetic testing when no therapeutic intervention is available. Recent work in mice provides a glimmer of hope that this might not always be true. Budworth et al. knew that the enzyme OGG1 is involved in DNA repair and, as a by-product, contributes to Htt-repeat instability. Because loss of OGG1 activity prevents somatic expansion of Htt repeats, Budworth et al. used this as a tool to explore in mice the role of somatic expansion in the age of onset of Huntington disease. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors’ Corner Source Type: research

Alternative Splicing QTLs in European and African Populations
With the advent of RNA-sequencing technology, we can detect different types of alternative splicing and determine how DNA variation regulates splicing. However, given the short read lengths used in most population-based RNA-sequencing experiments, quantifying transcripts accurately remains a challenge. Here we present a method, Altrans, for discovery of alternative splicing quantitative trait loci (asQTLs). To assess the performance of Altrans, we compared it to Cufflinks and MISO in simulations and Cufflinks for asQTL discovery. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Halit Ongen, Emmanouil T. Dermitzakis Tags: Article Source Type: research

Imputation of KIR Types from SNP Variation Data
Large population studies of immune system genes are essential for characterizing their role in diseases, including autoimmune conditions. Of key interest are a group of genes encoding the killer cell immunoglobulin-like receptors (KIRs), which have known and hypothesized roles in autoimmune diseases, resistance to viruses, reproductive conditions, and cancer. These genes are highly polymorphic, which makes typing expensive and time consuming. Consequently, despite their importance, KIRs have been little studied in large cohorts. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Damjan Vukcevic, James A. Traherne, Sigrid Næss, Eva Ellinghaus, Yoichiro Kamatani, Alexander Dilthey, Mark Lathrop, Tom H. Karlsen, Andre Franke, Miriam Moffatt, William Cookson, John Trowsdale, Gil McVean, Stephen Sawcer, Stephen Leslie Tags: Article Source Type: research

This Month in
Hereditary hemochromatosis (HH), a common genetic disorder in individuals with European ancestry, is characterized by aberrantly high absorption of dietary iron. Without appropriate intervention, HH can cause a variety of health problems, including cirrhosis, hepatocellular carcinoma, diabetes, and heart disease. Most cases of HH are caused by mutations in HFE, but the penetrance of these mutations remains unclear. Owing to this uncertainty, the American College of Medical Genetics and Genomics currently does not recommend evaluation or return of results for HFE incidental findings. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 1, 2015 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors’ Corner Source Type: research

Biallelic Mutations in Nuclear Pore Complex Subunit Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome
The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high ...
Source: The American Journal of Human Genetics - September 24, 2015 Category: Genetics & Stem Cells Authors: Noriko Miyake, Hiroyasu Tsukaguchi, Eriko Koshimizu, Akemi Shono, Satoko Matsunaga, Masaaki Shiina, Yasuhiro Mimura, Shintaro Imamura, Tomonori Hirose, Koji Okudela, Kandai Nozu, Yuko Akioka, Motoshi Hattori, Norishige Yoshikawa, Akiko Kitamura, Hae Il C Tags: Article Source Type: research

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes and
Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 17, 2015 Category: Genetics & Stem Cells Authors: Ilham Ratbi, Kim D. Falkenberg, Manou Sommen, Nada Al-Sheqaih, Soukaina Guaoua, Geert Vandeweyer, Jill E. Urquhart, Kate E. Chandler, Simon G. Williams, Neil A. Roberts, Mustapha El Alloussi, Graeme C. Black, Sacha Ferdinandusse, Hind Ramdi, Audrey Tags: Article Source Type: research

Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex
Multiciliated epithelial cells protect the upper and lower airways from chronic bacterial infections by moving mucus and debris outward. Congenital disorders of ciliary beating, referred to as primary ciliary dyskinesia (PCD), are characterized by deficient mucociliary clearance and severe, recurrent respiratory infections. Numerous genetic defects, most of which can be detected by transmission electron microscopy (TEM), are so far known to cause different abnormalities of the ciliary axoneme. However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved. (Sour...
Source: The American Journal of Human Genetics - September 17, 2015 Category: Genetics & Stem Cells Authors: Heike Olbrich, Carolin Cremers, Niki T. Loges, Claudius Werner, Kim G. Nielsen, June K. Marthin, Maria Philipsen, Julia Wallmeier, Petra Pennekamp, Tabea Menchen, Christine Edelbusch, Gerard W. Dougherty, Oliver Schwartz, Holger Thiele, Janine Altmül Tags: Article Source Type: research

Loss-of-Function Mutations in the WNT Co-receptor Cause Autosomal-Dominant Oligodontia
Tooth agenesis is one of the most common developmental anomalies in man. Oligodontia, a severe form of tooth agenesis, occurs both as an isolated anomaly and as a syndromal feature. We performed exome sequencing on 20 unrelated individuals with apparent non-syndromic oligodontia and failed to detect mutations in genes previously associated with oligodontia. In three of the probands, we detected heterozygous variants in LRP6, and sequencing of additional oligodontia-affected individuals yielded one additional mutation in LRP6. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 17, 2015 Category: Genetics & Stem Cells Authors: Maarten P.G. Massink, Marijn A. Créton, Francesca Spanevello, Willem M.M. Fennis, Marco S. Cune, Sanne M.C. Savelberg, Isaäc J. Nijman, Madelon M. Maurice, Marie-José H. van den Boogaard, Gijs van Haaften Tags: Report Source Type: research

Identification of a Recognizable Progressive Skeletal Dysplasia Caused by Mutations
We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 10, 2015 Category: Genetics & Stem Cells Authors: Maha Faden, Fatema AlZahrani, Roberto Mendoza-Londono, Lucie Dupuis, Taila Hartley, Peter Kannu, Julian A. Raiman, Andrew Howard, Wen Qin, Martine Tetreault, Joan Qiongchao Xi, Imadeddin Al-Thamer, Care4Rare Canada Consortium, Richard L. Maas, Kym Boyc Tags: Report Source Type: research

Penetrance of Hemochromatosis in Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network
Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygot...
Source: The American Journal of Human Genetics - September 10, 2015 Category: Genetics & Stem Cells Authors: Carlos J. Gallego, Amber Burt, Agnes S. Sundaresan, Zi Ye, Christopher Shaw, David R. Crosslin, Paul K. Crane, S. Malia Fullerton, Kris Hansen, David Carrell, Helena Kuivaniemi, Kimberly Derr, Mariza de Andrade, Catherine A. McCarty, Terrie E. Kit Tags: Article Source Type: research

Genetic Defects in Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia
The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 10, 2015 Category: Genetics & Stem Cells Authors: Sofie Symoens, Aileen M. Barnes, Charlotte Gistelinck, Fransiska Malfait, Brecht Guillemyn, Wouter Steyaert, Delfien Syx, Sanne D’hondt, Martine Biervliet, Julie De Backer, Eckhard P. Witten, Sergey Leikin, Elena Makareeva, Gabriele Gillessen-Kaesbac Tags: Article Source Type: research

Truncating Mutations of , a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis
Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the pa...
Source: The American Journal of Human Genetics - September 10, 2015 Category: Genetics & Stem Cells Authors: Dan Mejlachowicz, Flora Nolent, Jérome Maluenda, Hanitra Ranjatoelina-Randrianaivo, Fabienne Giuliano, Ivo Gut, Damien Sternberg, Annie Laquerrière, Judith Melki Tags: Report Source Type: research

A Genetic-Pathophysiological Framework for Craniosynostosis
Craniosynostosis, the premature fusion of one or more cranial sutures of the skull, provides a paradigm for investigating the interplay of genetic and environmental factors leading to malformation. Over the past 20 years molecular genetic techniques have provided a new approach to dissect the underlying causes; success has mostly come from investigation of clinical samples, and recent advances in high-throughput DNA sequencing have dramatically enhanced the study of the human as the preferred “model organism.” In parallel, however, we need a pathogenetic classification to describe the pathways and processes tha...
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Stephen R.F. Twigg, Andrew O.M. Wilkie Tags: Review Source Type: research

Gain-of-Function Mutations in Are Associated with Coronal Craniosynostosis and Learning Disability
We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Stephen R.F. Twigg, Jennifer Forecki, Jacqueline A.C. Goos, Ivy C.A. Richardson, A. Jeannette M. Hoogeboom, Ans M.W. van den Ouweland, Sigrid M.A. Swagemakers, Maarten H. Lequin, Daniel Van Antwerp, Simon J. McGowan, Isabelle Westbury, Kerry  Tags: Article Source Type: research

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents
(The American Journal of Human Genetics 97, 6–21; July 2, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Jeffrey R. Botkin, John W. Belmont, Jonathan S. Berg, Benjamin E. Berkman, Yvonne Bombard, Ingrid A. Holm, Howard P. Levy, Kelly E. Ormond, Howard M. Saal, Nancy B. Spinner, Benjamin S. Wilfond, Joseph D. McInerney Tags: Erratum Source Type: research

Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling
The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. However, the underlying molecular mechanism(s) remains unknown. Here, we show that ARID1B is a repressor of Wnt/β-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/β-catenin target genes are upregulated. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Georgia Vasileiou, Arif B. Ekici, Steffen Uebe, Christiane Zweier, Juliane Hoyer, Hartmut Engels, Jürgen Behrens, André Reis, Michel V. Hadjihannas Tags: Article Source Type: research

De Novo Mutations in Cause Intellectual Disability with Severe Speech Impairment
CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 3, 2015 Category: Genetics & Stem Cells Authors: Maja Hempel, Kirsten Cremer, Charlotte W. Ockeloen, Klaske D. Lichtenbelt, Johanna C. Herkert, Jonas Denecke, Tobias B. Haack, Alexander M. Zink, Jessica Becker, Eva Wohlleber, Jessika Johannsen, Bader Alhaddad, Rolph Pfundt, Sigrid Fuchs, Dagmar Wie Tags: Report Source Type: research