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Missense variants & pathogenicity prediction

Yanhan Deng, Zongzhe Li, Juan Liu, Zheng Wang, Yanyan Cao, Yong Mou, Bohua Fu, Biwen Mo, Jianghong Wei, Zhenshun Cheng, Liman Luo, Jingping Li, Ying Shu, Xiaomei Wang, Guangwei Luo, Shuo Yang, Yingnan Wang, Jing Zhu, Jingping Yang, Ming Wu, Xuyan Xu, Renying Ge, Xueqin Chen, Qingzhen Peng, Guang Wei, Yaqing Li, Hua Yang, Shirong Fang, Xiaoju Zhang, Weining Xiong
Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing...
June 19, 2018: Human Mutation
Boris Chaumette, Vladimir Ferrafiat, Amirthagowri Ambalavanan, Alice Goldenberg, Alexandre Dionne-Laporte, Dan Spiegelman, Patrick A Dion, Priscille Gerardin, Claudine Laurent, David Cohen, Judith Rapoport, Guy A Rouleau
Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified...
June 12, 2018: Molecular Psychiatry
Sneha P, Elaheh Ahmad Ebrahimi, Sara Ahmed Ghazala, Thirumal Kumar D, Siva R, George Priya Doss C, Hatem Zayed
Galactosemia type 2 is an autosomal recessive disorder characterized by the deficiency of galactokinase (GALK) enzyme due to missense mutations in GALK1 gene, which is associated with various manifestations such as hyper galactosemia and formation of cataracts. GALK enzyme catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of α-d-galactose to galactose-1-phosphate. We searched 4 different literature databases (Google Scholar, PubMed, PubMed Central, and Science Direct) and 3 gene-variant databases (Online Mendelian Inheritance in Man, Human Gene Mutation Database, and UniProt) to collect all the reported missense mutations associated with GALK deficiency...
June 12, 2018: Journal of Cellular Biochemistry
Muhammad Shakeel, Muhammad Irfan, Ishtiaq Ahmad Khan
Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system...
June 7, 2018: Gene
Steven N Hart, Tanya Hoskin, Hermela Shimelis, Raymond M Moore, Bingjian Feng, Abigail Thomas, Noralane M Lindor, Eric C Polley, David E Goldgar, Edwin Iversen, Alvaro N A Monteiro, Vera J Suman, Fergus J Couch
PURPOSE: To improve methods for predicting the impact of missense variants of uncertain significance (VUS) in BRCA1 and BRCA2 on protein function. METHODS: Functional data for 248 BRCA1 and 207 BRCA2 variants from assays with established high sensitivity and specificity for damaging variants were used to recalibrate 40 in silico algorithms predicting the impact of variants on protein activity. Additional random forest (RF) and naïve voting method (NVM) metapredictors for both BRCA1 and BRCA2 were developed to increase predictive accuracy...
June 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Eugenia Fraile-Bethencourt, Alberto Valenzuela-Palomo, Beatriz Díez-Gómez, Alberto Acedo, Eladio A Velasco
Genetic testing of BRCA1 and BRCA2 identifies a large number of variants of uncertain clinical significance whose functional and clinical interpretations pose a challenge for genetic counseling. Interestingly, a relevant fraction of DNA variants can disrupt the splicing process in cancer susceptibility genes. We have tested more than 200 variants throughout 19 BRCA2 exons mostly by minigene assays, 54% of which displayed aberrant splicing, thus confirming the utility of this assay to check genetic variants in the absence of patient RNA...
2018: Frontiers in Genetics
Lihua Lyu, Qiufeng Wang, Shujie Song, Huaibin Zhou, Ming Li, Chen Zhou, Zhiying Jiang, Liyan Li, Jianxin Lyu, Guorong Chen, Yidong Bai
This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.
April 2018: Data in Brief
Christina Zeitz, Cécile Méjécase, Mathilde Stévenard, Christelle Michiels, Isabelle Audo, Michael F Marmor
Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c...
2018: BioMed Research International
Karen S Raraigh, Sangwoo T Han, Emily Davis, Taylor A Evans, Matthew J Pellicore, Allison F McCague, Anya T Joynt, Zhongzhou Lu, Melis Atalar, Neeraj Sharma, Molly B Sheridan, Patrick R Sosnay, Garry R Cutting
Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression...
June 7, 2018: American Journal of Human Genetics
Bhavna S Rao, Samdani Ansar, Tharigopala Arokiasamy, Rachapalli R Sudhir, Vetrivel Umashankar, Rama Rajagopal, Nagasamy Soumittra
BACKGROUND: Fuchs' endothelial corneal dystrophy (FECD) is a complex degenerative disease of the corneal endothelium with genetic predisposition. Pathogenic rare variants have been identified in SLC4A11, LOXHD1, ZEB1, and AGBL1. Association of single nucleotide polymorphisms (SNPs) and CTG trinucleotide repeat expansions in the intron of TCF4 gene to FECD has been studied across multiple ethnicities. Recently, genome-wide association studies have also identified KANK4, LAMC1, and ATP1B1 as novel loci for FECD...
May 25, 2018: Ophthalmic Genetics
Cristina Fortuno, Paul A James, Erin L Young, Bing Feng, Magali Olivier, Tina Pesaran, Sean V Tavtigian, Amanda B Spurdle
Clinical interpretation of germline missense variants represents a major challenge, including those in the TP53 Li-Fraumeni syndrome gene. Bioinformatic prediction is a key part of variant classification strategies. We aimed to optimize the performance of the Align-GVGD tool used for p53 missense variant prediction, and compare its performance to other bioinformatic tools (SIFT, PolyPhen-2) and ensemble methods (REVEL, BayesDel). Reference sets of assumed pathogenic and assumed benign variants were defined using functional and/or clinical data...
May 18, 2018: Human Mutation
Nikolai Paul Pace, Johann Craus, Alex Felice, Josanne Vassallo
BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy...
May 15, 2018: BMC Endocrine Disorders
Xuan Cui, Ruben Jauregui, Karen Sophia Park, Stephen H Tsang
PURPOSE: Gyrate atrophy (GA) is a rare chorioretinal degeneration that results in the deterioration of night and peripheral vision, eventually leading to blindness. The disorder is caused by mutations in the gene encoding ornithine aminotransferase (OAT), causing increased levels of plasma ornithine. Treatment revolves around lowering plasma ornithine levels, with vitamin B6 supplementation being the preferred treatment. Nevertheless, most patients do not respond to this therapy. Here, we report a rare case of vitamin B6-responsive GA caused by a novel mutation in OAT and characterize the presentation with multimodal imaging...
May 14, 2018: Ophthalmic Genetics
Mieke Wesdorp, Pia A M de Koning Gans, Margit Schraders, Jaap Oostrik, Martijn A Huynen, Hanka Venselaar, Andy J Beynon, Judith van Gaalen, Vitória Piai, Nicol Voermans, Michelle M van Rossum, Bas P Hartel, Stefan H Lelieveld, Laurens Wiel, Berit Verbist, Liselotte J Rotteveel, Marieke F van Dooren, Peter Lichtner, Henricus P M Kunst, Ilse Feenstra, Ronald J C Admiraal, Helger G Yntema, Lies H Hoefsloot, Ronald J E Pennings, Hannie Kremer
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions...
May 12, 2018: Human Genetics
Jennifer L Smith, David J Tester, Allison R Hall, Don E Burgess, Chun-Chun Hsu, Samy Claude Elayi, Corey L Anderson, Craig T January, Jonathan Z Luo, Dustin N Hartzel, Uyenlinh L Mirshahi, Michael F Murray, Tooraj Mirshahi, Michael J Ackerman, Brian P Delisle
BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R...
May 2018: Circulation. Arrhythmia and Electrophysiology
Hongchun Du, Yubiao Guo, Di Ma, Kejing Tang, Decheng Cai, Yifeng Luo, Canmao Xie
RATIONALE: Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear...
May 2018: Medicine (Baltimore)
Jia Chen, Xiaoxin Li, Yuchen Niu, Zhihong Wu, Guixing Qiu
BACKGROUND The present study aimed to evaluate the pathogenicity of 5 [i]GDF3[/i] gene variations using functional and [i]in silico[/i] assessment approaches in a Chinese congenital scoliosis population. MATERIAL AND METHODS We selected 13 patients carrying 5 variants from a congenital scoliosis cohort. The PCR products of samples were verified by Sanger sequencing. The data and sequence alignment were analyzed using Chromas and ClustalW. SIFT and PolyPhen-2 were used to predict the functional effects of each missense and amino acid substitutions...
May 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Suzanna G M Frints, Aysegul Ozanturk, Germán Rodríguez Criado, Ute Grasshoff, Bas de Hoon, Michael Field, Sylvie Manouvrier-Hanu, Scott E Hickey, Molka Kammoun, Karen W Gripp, Claudia Bauer, Christopher Schroeder, Annick Toutain, Theresa Mihalic Mosher, Benjamin J Kelly, Peter White, Andreas Dufke, Eveline Rentmeester, Sungjin Moon, Daniel C Koboldt, Kees E P van Roozendaal, Hao Hu, Stefan A Haas, Hans-Hilger Ropers, Lucinda Murray, Eric Haan, Marie Shaw, Renee Carroll, Kathryn Friend, Jan Liebelt, Lynne Hobson, Marjan De Rademaeker, Joep Geraedts, Jean-Pierre Fryns, Joris Vermeesch, Martine Raynaud, Olaf Riess, Joost Gribnau, Nicholas Katsanis, Koen Devriendt, Peter Bauer, Jozef Gecz, Christelle Golzio, Cristina Gontan, Vera M Kalscheuer
RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations...
May 4, 2018: Molecular Psychiatry
Ivana Nedeljkovic, Natalie Terzikhan, Judith M Vonk, Diana A van der Plaat, Lies Lahousse, Cleo C van Diemen, Brian D Hobbs, Dandi Qiao, Michael H Cho, Guy G Brusselle, Dirkje S Postma, H M Boezen, Cornelia M van Duijn, Najaf Amin
Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak...
2018: Frontiers in Genetics
Laura Lucchetti, Paolo Prontera, Amedea Mencarelli, Ester Sallicandro, Annalisa Mencarelli, Marta Cofini, Alberto Leonardi, Gabriela Stangoni, Laura Penta, Susanna Esposito
Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance...
2018: Frontiers in Endocrinology
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