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Human Mutation

Lishuang Shen, Marcella Attimonelli, Renkui Bai, Marie T Lott, Douglas C Wallace, Marni J Falk, Xiaowu Gai
Accurate mitochondrial DNA (mtDNA) variant annotation is essential for the clinical diagnosis of diverse human diseases. Substantial challenges to this process include the inconsistency in mtDNA nomenclatures, the existence of multiple reference genomes, and a lack of reference population frequency data. Clinicians need a simple bioinformatics tool that is user-friendly, and bioinformaticians need a powerful informatics resource for programmatic usage. Here, we report the development and functionality of the MSeqDR mtDNA Variant Tool set (mvTool), a one-stop mtDNA variant annotation and analysis web service...
March 14, 2018: Human Mutation
Kathryn B Manheimer, Nihir Patel, Felix Richter, Joshua Gorham, Angela C Tai, Jason Homsy, Marko T Boskovski, Michael Parfenov, Elizabeth Goldmuntz, Wendy K Chung, Martina Brueckner, Martin Tristani-Firouzi, Deepak Srivastava, Jonathan G Seidman, Christine E Seidman, Bruce D Gelb, Andrew J Sharp
Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs)...
March 11, 2018: Human Mutation
Patrice Bourgeois, Clothilde Esteve, Charlène Chaix, Christophe Béroud, Nicolas Levy, Alexandre Fabre, Catherine Badens
Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in mammals nor of the pathophysiology of the disease. Since the identification of the genes, we have set up the molecular diagnostic of THES in routine, gathering a large cohort with clinical and molecular data. Here, we report the phenotype and genotype analysis of this cohort together with an extensive literature review of THES cases worldwide, ie 96 individuals harboring mutations in one gene or the other...
March 11, 2018: Human Mutation
Rivka Sukenik Halevy, Huan-Chieh Chien, Bo Heinz, Michael J Bamshad, Deborah A Nickerson, Martin Kircher, Nadav Ahituv
Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly...
March 10, 2018: Human Mutation
Deeann Wallis, Kairong Li, Hui Lui, Ke Hu, Mei-Jan Chen, Jing Li, Jungsoon Kang, Shamik Das, Bruce R Korf, Robert A Kesterson
Neurofibromatosis type 1 (NF1; MIM# 613113) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a >250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells...
March 9, 2018: Human Mutation
Ulrike Schindlbeck, Thomas Wittmann, Stefanie Höppner, Susanna Kinting, Gerhard Liebisch, Jan Hegermann, Matthias Griese
Mutations in the ATP-binding cassette subfamily A member 3 (ABCA3) gene are the most common monogenetic cause of surfactant dysfunction disorders in newborns and interstitial lung diseases in children and young adults. Whereas the effect of mutations resulting in truncated or incomplete proteins can be predicted, the consequences of missense variants cannot be as easily. Our aim was to investigate the intracellular handling and disturbance of the cellular surfactant system in a stable cell model with several different clinically relevant ABCA3 missense mutations...
March 5, 2018: Human Mutation
Yongchu Pan, Dandan Li, Shu Lou, Chi Zhang, Yifei Du, Hongbing Jiang, Weibing Zhang, Lan Ma, Lin Wang
microRNAs (miRNAs) are widely involved in craniofacial development, and genetic variants of miRNAs may be associated with the risk of non-syndromic orofacial cleft (NSOC). Here, we systematically selected five single nucleotide polymorphisms (SNPs) of miRNAs and investigated the associations between these variants and NSOC susceptibility in a two-stage case-control study including 1,406 NSOC patients and 1,578 controls from the Chinese population. We found that compared with the C allele, the rs2910164 G allele of pre-miR-146a was associated with an increased risk of NSOC (additive model: odds ratio (OR) = 1...
February 27, 2018: Human Mutation
Cima Saghira, Dana M Bis, David Stanek, Alleene Strickland, David N Herrmann, Mary M Reilly, Steven S Scherer, Michael E Shy, Stephan Züchner
Charcot-Marie-Tooth disease (CMT) is an umbrella term for inherited neuropathies affecting an estimated one in 2,500 people. Over 120 CMT and related genes have been identified and clinical gene panels often contain more than 100 genes. Such a large genomic space will invariantly yield variants of uncertain clinical significance (VUS) in nearly any person tested. This rise in number of VUS creates major challenges for genetic counseling. Additionally, fewer individual variants in known genes are being published as the academic merit is decreasing, and most testing now happens in clinical laboratories, which typically do not correlate their variants with clinical phenotypes...
February 22, 2018: Human Mutation
Mara Colombo, Irene Lòpez-Perolio, Huong D Meeks, Laura Caleca, Michael Parsons, Hongyan Li, Giovanna De Vecchi, Emma Tudini, Claudia Foglia, Patrizia Mondini, Siranoush Manoukian, Raquel Behar, Encarna B Gomez Garcia, Alfons Meindl, Marco Montagna, Dieter Niederacher, Ane Y Schmidt, Liliana Varesco, Barbara Wappenschmidt, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Alicia Beeghly-Fadel, Javier Benitez, Bram Boeckx, Natalia V Bogdanova, Stig E Bojesen, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude, Don M Conroy, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Mikael Eriksson, Peter A Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Montserrat García-Closas, Graham G Giles, Anna González-Neira, Pascal Guénel, Christopher A Haiman, Per Hall, Ute Hamann, Mikael Hartman, Jan Hauke, Antoinette Hollestelle, John L Hopper, Anna Jakubowska, Audrey Jung, Veli-Matti Kosma, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubinski, Arto Mannermaa, Sara Margolin, Hui Miao, Roger L Milne, Susan L Neuhausen, Heli Nevanlinna, Janet E Olson, Paolo Peterlongo, Julian Peto, Katri Pylkäs, Elinor J Sawyer, Marjanka K Schmidt, Rita K Schmutzler, Andreas Schneeweiss, Minouk J Schoemaker, Mee Hoong See, Melissa C Southey, Anthony Swerdlow, Soo H Teo, Amanda E Toland, Ian Tomlinson, Thérèse Truong, Christi J van Asperen, Ans M W van den Ouweland, Lizet van der Kolk, Robert Winqvist, Drakoulis Yannoukakos, Wei Zheng, Alison M Dunning, Douglas F Easton, Alex Henderson, Frans Hogervorst, Louise Izatt, Kenneth Offitt, Lucy E Side, Elizabeth J van Rensburg, Study Embrace, Study Hebon, Lesley McGuffog, Antonis C Antoniou, Georgia Chenevix-Trench, Amanda B Spurdle, David E Goldgar, Miguel de la Hoya, Paolo Radice
Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families...
February 20, 2018: Human Mutation
Jake R Saklatvala, Nick Dand, Michael A Simpson
The genetic diagnosis of rare monogenic diseases using exome/genome sequencing requires the true causal variant(s) to be identified from tens of thousands of observed variants. Typically a virtual gene panel approach is taken whereby only variants in genes known to cause phenotypes resembling the patient under investigation are considered. With the number of known monogenic gene-disease pairs exceeding 5000, manual curation of personalised virtual panels using exhaustive knowledge of the genetic basis of the human monogenic phenotypic spectrum is challenging...
February 20, 2018: Human Mutation
Timothy R Rebbeck, Tara M Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, Ava Kwong, Edith Olah, Olufunmilayo I Olopade, Angela R Solano, Soo-Hwang Teo, Mads Thomassen, Jeffrey N Weitzel, T L Chan, Fergus J Couch, David E Goldgar, Torben A Kruse, Edenir Inêz Palmero, Sue Kyung Park, Diana Torres, Elizabeth J van Rensburg, Lesley McGuffog, Michael T Parsons, Goska Leslie, Cora M Aalfs, Julio Abugattas, Julian Adlard, Simona Agata, Kristiina Aittomäki, Lesley Andrews, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Banu K Arun, Ella Asseryanis, Leo Auerbach, Jacopo Azzollini, Judith Balmaña, Monica Barile, Rosa B Barkardottir, Daniel Barrowdale, Javier Benitez, Andreas Berger, Raanan Berger, Amie M Blanco, Kathleen R Blazer, Marinus J Blok, Valérie Bonadona, Bernardo Bonanni, Angela R Bradbury, Carole Brewer, Bruno Buecher, Saundra S Buys, Trinidad Caldes, Almuth Caliebe, Maria A Caligo, Ian Campbell, Sandrine Caputo, Jocelyne Chiquette, Wendy K Chung, Kathleen B M Claes, J Margriet Collée, Jackie Cook, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Antoine de Pauw, Capucine Delnatte, Orland Diez, Yuan Chun Ding, Nina Ditsch, Susan M Domchek, Cecilia M Dorfling, Carolina Velazquez, Bernd Dworniczak, Jacqueline Eason, Douglas F Easton, Ros Eeles, Hans Ehrencrona, Bent Ejlertsen, Christoph Engel, Stefanie Engert, D Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Sandra Fert Ferrer, Lenka Foretova, Jeffrey Fowler, Debra Frost, Henrique C R Galvão, Patricia A Ganz, Judy Garber, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Sophie Giraud, Gord Glendon, Andrew K Godwin, Mark H Greene, Jacek Gronwald, Angelica Gutierrez-Barrera, Eric Hahnen, Jan Hauke, Alex Henderson, Julia Hentschel, Frans B L Hogervorst, Ellen Honisch, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M John, Vijai Joseph, Katarzyna Kaczmarek, Beth Y Karlan, Karin Kast, KConFab Investigators, Sung-Won Kim, Irene Konstantopoulou, Jacob Korach, Yael Laitman, Adriana Lasa, Christine Lasset, Conxi Lázaro, Annette Lee, Min Hyuk Lee, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Noralane M Lindor, Michel Longy, Jennifer T Loud, Karen H Lu, Jan Lubinski, Eva Machackova, Siranoush Manoukian, Véronique Mari, Cristina Martínez-Bouzas, Zoltan Matrai, Noura Mebirouk, Hanne E J Meijers-Heijboer, Alfons Meindl, Arjen R Mensenkamp, Ugnius Mickys, Austin Miller, Marco Montagna, Kirsten B Moysich, Anna Marie Mulligan, Jacob Musinsky, Susan L Neuhausen, Heli Nevanlinna, Joanne Ngeow, Huu Phuc Nguyen, Dieter Niederacher, Henriette Roed Nielsen, Finn Cilius Nielsen, Robert L Nussbaum, Kenneth Offit, Anna Öfverholm, Kai-Ren Ong, Ana Osorio, Laura Papi, Janos Papp, Barbara Pasini, Inge Sokilde Pedersen, Ana Peixoto MSc, Nina Peruga MSc, Paolo Peterlongo, Esther Pohl, Nisha Pradhan Ba, Karolina Prajzendanc, Fabienne Prieur, Pascal Pujol, Paolo Radice, Susan J Ramus, Johanna Rantala, Muhammad Usman Rashid, Kerstin Rhiem, Mark Robson, Gustavo C Rodriguez, Mark T Rogers, Vilius Rudaitis, Ane Y Schmidt, Rita Katharina Schmutzler, Leigha Senter, Payal D Shah, Priyanka Sharma, Lucy E Side, Jacques Simard, Christian F Singer, Anne-Bine Skytte, Thomas P Slavin, Katie Snape, Hagay Sobol, Melissa Southey, Linda Steele, Doris Steinemann, Grzegorz Sukiennicki, Christian Sutter, Csilla I Szabo, Yen Y Tan, Manuel R Teixeira, Mary Beth Terry, Alex Teulé, Abigail Thomas, Darcy L Thull, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Sabine Topka, Alison H Trainer, Nadine Tung, Christi J van Asperen, Annemieke H van der Hout, Lizet E van der Kolk, Rob B van der Luijt, Mattias Van Heetvelde, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Cynthia Villarreal-Garza, Anna von Wachenfeldt, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H F Weber, Drakoulis Yannoukakos, Sook-Yee Yoon, Cristina Zanzottera, Jamal Zidan, Kristin K Zorn, Christina G Hutten Selkirk, Peter J Hulick, Georgia Chenevix-Trench, Amanda B Spurdle, Antonis C Antoniou, Katherine L Nathanson
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on 6 continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database...
February 15, 2018: Human Mutation
Taimoor I Sheikh, Ricardo Harripaul, Muhammad Ayub, John B Vincent
Mutations in the Methyl-CpG-binding protein-2 gene (MECP2) are commonly associated with Rett syndrome. However, it has long been appreciated that there exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. The most frequent Rett missense mutations are located in either the methyl-CpG-binding domain (MBD) or transcription repression domain (TRD). Clinical roles for mutations in other domains such as the intervening domain (ID) or AT-Hook domains have yet to be determined. Here, we report functional analysis of MECP2 missense mutations, located in AT-Hook1 within the ID, in a large Pakistani family with childhood onset cognitive decline and schizophrenia, de novo in a girl with atypical Rett syndrome, and de novo in a woman with schizophrenia...
February 12, 2018: Human Mutation
Zuzana Slamova, Lusine Nazaryan-Petersen, Mana M Mehrjouy, Jana Drabova, Miroslava Hancarova, Tatana Marikova, Drahuse Novotna, Marketa Vlckova, Zdenka Vlckova, Mads Bak, Zuzana Zemanova, Niels Tommerup, Zdenek Sedlacek
Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0...
February 6, 2018: Human Mutation
Dorien Schepers, Giada Tortora, Hiroko Morisaki, Gretchen MacCarrick, Mark Lindsay, David Liang, Sarju G Mehta, Jennifer Hague, Judith Verhagen, Ingrid van de Laar, Marja Wessels, Yvonne Detisch, Mieke van Haelst, Annette Baas, Klaske Lichtenbelt, Kees Braun, Denise van der Linde, Jolien Roos-Hesselink, George McGillivray, Josephina Meester, Isabelle Maystadt, Paul Coucke, Elie El-Khoury, Sandhya Parkash, Birgitte Diness, Lotte Risom, Ingrid Scurr, Yvonne Hilhorst-Hofstee, Takayuki Morisaki, Julie Richer, Julie Désir, Marlies Kempers, Andrea L Rideout, Gabrielle Horne, Chris Bennett, Elisa Rahikkala, Geert Vandeweyer, Maaike Alaerts, Aline Verstraeten, Hal Dietz, Lut Van Laer, Bart Loeys
The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS...
February 1, 2018: Human Mutation
Mattia Ferrarese, Maria Francesca Testa, Dario Balestra, Francesco Bernardi, Mirko Pinotti, Alessio Branchini
Pre-peptide regions of secreted proteins display wide sequence variability, even among highly homologous proteins such as coagulation factors, and are intracellularly removed, thus potentially favouring secretion of wild-type proteins upon suppression of nonsense mutations (translational readthrough). As models we selected F9 nonsense mutations with readthrough-favourable features affecting the pre-peptide and pro-peptide regions of coagulation factor IX (FIX), which cause Hemophilia B. Only the p.Gly21Ter (c...
February 1, 2018: Human Mutation
T Paff, I E Kooi, Y Moutaouakil, E Riesebos, E A Sistermans, J M A Daniels, M M Weiss, H W M Niessen, E G Haarman, G Pals, D Micha
We aimed to determine the diagnostic yield of a targeted-exome panel in a cohort of 74 Dutch primary ciliary dyskinesia (PCD) patients. The panel consisted of 26 PCD-related and 284 candidate genes. To prioritize PCD candidate genes, we investigated the transcriptome of human airway cells of twelve healthy volunteers during in vitro ciliogenesis and hypothesized that PCD-related genes show significant upregulation. We compared gene expression in epithelial precursor cells grown as collagen monolayer and ciliated cells grown in suspension by RNA sequencing...
January 23, 2018: Human Mutation
Valerie K Jordan, Brieana Fregeau, Xiaoyan Ge, Jessica Giordano, Ronald J Wapner, Tugce B Balci, Melissa T Carter, John A Bernat, Amanda N Moccia, Anshika Srivastava, Donna M Martin, Stephanie L Bielas, John Pappas, Melissa D Svoboda, Marlène Rio, Nathalie Boddaert, Vincent Cantagrel, Andrea M Lewis, Fernando Scaglia, Jennefer N Kohler, Jonathan A Bernstein, Annika M Dries, Jill A Rosenfeld, Colette DeFilippo, Willa Thorson, Yaping Yang, Elliott H Sherr, Weimin Bi, Daryl A Scott
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency...
January 13, 2018: Human Mutation
Katarzyna Skonieczna, Boris Malyarchuk, Arkadiusz Jawień, Andrzej Marszałek, Zbigniew Banaszkiewicz, Paweł Jarmocik, Tomasz Grzybowski
So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are "drivers" or "passengers" of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome...
January 12, 2018: Human Mutation
Kumari Alka, Joseph R Casey
SLC4A11 mutations cause cases of congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (HS), and Fuchs endothelial corneal dystrophy (FECD). Defective water reabsorption from corneal stroma by corneal endothelial cells (CECs) leads to these corneal dystrophies. SLC4A11, in the CEC basolateral membrane facilitates transmembrane movement of H2 O, NH3 and H+ -equivalents. Some SLC4A11 disease mutants have impaired folding, leading to a failure to move to the cell surface, which in some cases can be corrected by the drug, Glafenine...
January 11, 2018: Human Mutation
A Coppe, L Nogara, M S Pizzuto, A Cani, S Cesaro, R Masetti, F Locatelli, G Te Kronnie, G Basso, S Bortoluzzi, S Bresolin
The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott-Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X-linked neutropenia (XLN). Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present Juvenile MyeloMonocytic Lukemia (JMML)-like features, confounding differential diagnosis above all in the co-presence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients...
January 7, 2018: Human Mutation
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