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Yishuo Wu, Hongjie Yu, S Lilly Zheng, Rong Na, Mufaddal Mamawala, Tricia Landis, Kathleen Wiley, Jacqueline Petkewicz, Sameep Shah, Zhuqing Shi, Kristian Novakovic, Michael McGuire, Charles B Brendler, Qiang Ding, Brian T Helfand, H Ballentine Carter, Kathleen A Cooney, William B Isaacs, Jianfeng Xu
BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis...
March 9, 2018: Prostate
Alain Calender, Pierre Antoine Rollat Farnier, Adrien Buisson, Stéphane Pinson, Abderrazzaq Bentaher, Serge Lebecque, Harriet Corvol, Rola Abou Taam, Véronique Houdouin, Claire Bardel, Pascal Roy, Gilles Devouassoux, Vincent Cottin, Pascal Seve, Jean-François Bernaudin, Clarice X Lim, Thomas Weichhart, Dominique Valeyre, Yves Pacheco, Annick Clement, Nadia Nathan
BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr...
March 6, 2018: BMC Medical Genomics
Ágnes Molnár, Attila Patócs, István Likó, Gábor Nyírő, Károly Rácz, Miklós Tóth, Beatrix Sármán
BACKGROUND: Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids. CASE PRESENTATION: A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone...
March 6, 2018: BMC Medical Genetics
Christian Niederwanger, Silvia Lechner, Lisa König, Andreas R Janecke, Claus Pototschnig, Beatrice Häussler, Sabine Scholl-Bürgi, Thomas Müller, Peter Heinz-Erian
BACKGROUND: Choanal (CA) and gastrointestinal atresias (GA) are an important feature of syndromic congenital sodium diarrhea (sCSD), a disorder recently associated with mutations in the gene for serine protease inhibitor type 2 (SPINT2). It is, however, not known whether isolated non-syndromic CA and GA themselves might result from SPINT2 mutations. METHODS: We performed a prospective cohort study to investigate 19 CA and/or GA patients without diarrhea ("non-sCSD") for potential sCSD characteristic clinical features and SPINT2 mutations...
March 2, 2018: European Journal of Medical Research
M Sébastien, B Ange-Line, A Mirna, C Martin, S Elisabeth, G Cyril, G Anne-Marie, C Aude, C Perrine, H Delphine, F Anne, H Nada, V Antonio, T-M-T Frédéric, P Christophe, D Yannis, T-R Christel, F Laurence
Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in OMIM genes and non-OMIM genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients, in order to identity novel MH-ID genes...
February 20, 2018: Clinical Genetics
Muhammad Shakeel, Muhammad Irfan, Ishtiaq Ahmad Khan
The deleterious genetic variants contributing to certain diseases may differ in terms of number and allele frequency from population to population depending on their evolutionary background. Here, we prioritize the deleterious variants from Pakistani population in manually curated gene list already reported to be associated with common, Mendelian, and congenital cardiovascular diseases (CVDs) using the genome/exome sequencing data of Pakistani individuals publically available in 1000 Genomes Project (PJL), and Exome Aggregation Consortium (ExAC) South Asia...
2018: PloS One
Daniele Cassatella, Sasha Howard, James Acierno, Cheng Xu, Georgios Papadakis, Federico A Santoni, Andrew A Dwyer, Sara Santini, Gerasimos Sykiotis, Caroline Chambion, Jenny Meylan, Laura Marino, Lucie Favre, Jiankang Li, Xuanzhu Liu, Jian-Guo Zhang, Pierre Bouloux, Christian De Geyter, Anne De Paepe, Waljit S Dhillo, Jean-Marc Ferrara, Michael Hauschild, Mariarosaria Lang-Muritano, Johannes Lemke, Christa E Flück, Attila Nemeth, Franziska Phan-Hug, Duarte Pignatelli, Vera Popovic, Sandra Pekic, Richard Quinton, Gabor Szinnai, Dagmar l'Allemand, Daniel Konrad, Saba Sharif, Özlem Turhan Iyidir, Brian J Stevenson, Huanming Yang, Leo Dunkel, Nelly Pitteloud
OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated with CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders...
February 1, 2018: European Journal of Endocrinology
Laura Andreasen, Gustav Ahlberg, Chuyi Tang, Charlotte Andreasen, Jacob P Hartmann, Jacob Tfelt-Hansen, Elijah R Behr, Steen Pehrson, Stig Haunsø, LuCamp, Peter E Weeke, Thomas Jespersen, Morten S Olesen, Jesper H Svendsen
Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases...
February 2, 2018: European Journal of Human Genetics: EJHG
Daniel J Pomerantz, Sacha Ferdinandusse, Joy Cogan, David N Cooper, Tyler Reimschisel, Amy Robertson, Anna Bican, Tracy McGregor, Jackie Gauthier, David S Millington, Jaime L W Andrae, Michael R Tschannen, Daniel C Helbling, Wendy M Demos, Simone Denis, Ronald J A Wanders, John N Newman, Rizwan Hamid, John A Phillips
Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD...
February 1, 2018: American Journal of Medical Genetics. Part A
Yu Zheng, Hai-Lin Wang, Jian-Kang Li, Li Xu, Laurent Tellier, Xiao-Lin Li, Xiao-Yan Huang, Wei Li, Tong-Tong Niu, Huan-Ming Yang, Jian-Guo Zhang, Dong-Ning Liu
AIM: To study the genes responsible for retinitis pigmentosa. METHODS: A total of 15 Chinese families with retinitis pigmentosa, containing 94 sporadically afflicted cases, were recruited. The targeted sequences were captured using the Target_Eye_365_V3 chip and sequenced using the BGISEQ-500 sequencer, according to the manufacturer's instructions. Data were aligned to UCSC Genome Browser build hg19, using the Burroughs Wheeler Aligner MEM algorithm. Local realignment was performed with the Genome Analysis Toolkit (GATK v...
2018: International Journal of Ophthalmology
Mahmoud Koko, Mohammed O E Abdallah, Mutaz Amin, Muntaser Ibrahim
BACKGROUND: The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling. RESULTS: More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles...
January 15, 2018: BMC Genomics
Ronald A Panganiban, Maoyun Sun, Amber Dahlin, Hae-Ryung Park, Mengyuan Kan, Blanca E Himes, Jennifer A Mitchel, Carlos Iribarren, Eric Jorgenson, Scott H Randell, Elliot Israel, Kelan Tantisira, Stephanie Shore, Jin-Ah Park, Scott T Weiss, Ann Chen Wu, Quan Lu
BACKGROUND: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. OBJECTIVES: We sought to identify and characterize functional variants in the 17q21 locus. METHODS: We used the Exome Aggregation Consortium (ExAC) browser to identify coding (amino acid-changing) variants in the 17q21 locus...
January 9, 2018: Journal of Allergy and Clinical Immunology
Caroline M Gorvin, Raghu Metpally, Victoria J Stokes, Fadil M Hannan, Sarath B Krishnamurthy, John D Overton, Jeffrey G Reid, Gerda E Breitwieser, Rajesh V Thakker
Mutations of the sigma subunit of the heterotetrameric adaptor-related protein complex 2 (AP2σ) impair signalling of the calcium-sensing receptor (CaSR), and cause familial hypocalciuric hypercalcaemia type 3 (FHH3). To date, FHH3-associated AP2σ mutations have only been identified at one residue, Arg15. We hypothesized that additional rare AP2σ variants may also be associated with altered CaSR function and hypercalcaemia, and sought for these by analysing >111,995 exomes (>60,706 from ExAc and dbSNP, and 51,289 from the Geisinger Health System-Regeneron DiscovEHR dataset which also contains clinical data)...
January 9, 2018: Human Molecular Genetics
Galuh D N Astuti, L Ingeborgh van den Born, M Imran Khan, Christian P Hamel, Béatrice Bocquet, Gaël Manes, Mathieu Quinodoz, Manir Ali, Carmel Toomes, Martin McKibbin, Mohammed E El-Asrag, Lonneke Haer-Wigman, Chris F Inglehearn, Graeme C M Black, Carel B Hoyng, Frans P M Cremers, Susanne Roosing
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs...
January 10, 2018: Genes
Camilo Toro, Roderick T Hori, May Christine V Malicdan, Cynthia J Tifft, Amy Goldstein, William A Gahl, David R Adams, Fauni Harper, Lynne A Wolfe, Jianfeng Xiao, Mohammad M Khan, Jun Tian, Kevin A Hope, Lawrence T Reiter, Michel G Tremblay, Thomas Moss, Alexis L Franks, Chris Balak, Mark S LeDoux
UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10:g.42290219C>T, NM_014233.3:c.628G>A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 yrs and characterized by slow progression of global motor, cognitive and behavioral dysfunction...
January 2, 2018: Human Molecular Genetics
Charlotta Pauline Irmgard Schärfe, Roman Tremmel, Matthias Schwab, Oliver Kohlbacher, Debora Susan Marks
BACKGROUND: Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classic pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. METHODS: Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional variants in 806 drug-related genes, including 628 known drug targets...
December 22, 2017: Genome Medicine
Yelena Bykhovskaya, Majid Fardaei, Mariam Lotfy Khaled, Mahmood Nejabat, Ramin Salouti, Hassan Dastsooz, Yutao Liu, Soroor Inaloo, Yaron S Rabinowitz
Purpose: To test candidate genes TSC1 and TSC2 in a family affected by tuberous sclerosis complex (TSC) where proband was also diagnosed with bilateral keratoconus (KC) and to test the hypothesis that defects in the same gene may lead to a nonsyndromic KC. Methods: Next-generation sequencing of TSC1 and TSC2 genes was performed in a proband affected by TSC and KC. Identified mutation was confirmed by Sanger DNA sequencing. Whole exome sequencing (WES) was performed in patients with nonsyndromic KC...
December 1, 2017: Investigative Ophthalmology & Visual Science
Nuno Rocha, Felicity Payne, Isabel Huang-Doran, Alison Sleigh, Katherine Fawcett, Claire Adams, Anna Stears, Vladimir Saudek, Stephen O'Rahilly, Inês Barroso, Robert K Semple
Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis...
December 14, 2017: Scientific Reports
Christian Paludan-Müller, Gustav Ahlberg, Jonas Ghouse, Jesper H Svendsen, Stig Haunsø, Morten S Olesen
BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database. METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706)...
December 2017: Circulation. Cardiovascular Genetics
Hande Kaymakcalan, Yanki Yarman, Nukte Goc, Fatih Toy, Cihan Meral, A Gulhan Ercan-Sencicek, Murat Gunel
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c...
February 2018: American Journal of Medical Genetics. Part A
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