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Human Mutation

Ellen F Macnamara, Alanna E Koehler, Precilla D'Souza, Tyra Estwick, Paul Lee, Gilbert Vezina, Harper Fauni, Stephen R Braddock, Erin Torti, James Matthew Holt, Prashant Sharma, May Christine V Malicdan, Cynthia J Tifft
Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22kb homozygous deletion in SLC12A2, which encodes for a sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia...
February 10, 2019: Human Mutation
Bong Jik Kim, Dong-Kyu Kim, Jin Hee Han, Jayoung Oh, Ah Reum Kim, Chung Lee, Nayoung Kd Kim, Hye-Rim Park, Min Young Kim, Sejoon Lee, Seungmin Lee, Doo Yi Oh, Woong-Yang Park, Sungjin Park, Byung Yoon Choi
Otoancorin (OTOA), encoded by OTOA, is required for the development of the tectorial membrane (TM) in the inner ear. Mutations in this gene cause non-syndromic hearing loss (DFNB22). The molecular mechanisms underlying most of DFNB22 remains poorly understood. Disruption of glycosylphosphatidylinositol (GPI) anchorage has been assumed to be the pathophysiology , mandating experimental validation. From a Korean deaf family, we identified two trans OTOA variants (c.1320+5G>C and p.Gln589ArgfsX55 (NM_144672...
February 10, 2019: Human Mutation
Richard Gallon, Barbara Mühlegger, Sören-Sebastian Wenzel, Harsh Sheth, Christine Hayes, Stefan Aretz, Karin Dahan, William Foulkes, Christian P Kratz, Tim Ripperger, Amedeo A Azizi, Hagit Baris Feldman, Anne-Laure Chong, Ugur Demirsoy, Benoît Florkin, Thomas Imschweiler, Danuta Januszkiewicz-Lewandowska, Stephan Lobitz, Michaela Nathrath, Hans-Jürgen Pander, Vanesa Perez-Alonso, Claudia Perne, Iman Ragab, Thorsten Rosenbaum, Daniel Rueda, Markus G Seidel, Manon Suerink, Julia Taeubner, Stefanie-Yvonne Zimmermann, Johannes Zschocke, Gillian M Borthwick, John Burn, Michael S Jackson, Mauro Santibanez-Koref, Katharina Wimmer
Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous paediatric malignancies, and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability (MSI) in non-neoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity...
February 10, 2019: Human Mutation
Guy M Lenk, Ian R Berry, Chloe A Stutterd, Moira Blyth, Lydia Green, Gayatri Vadlamani, Daniel Warren, Ian Craven, Miriam Fanjul-Fernandez, Victoria Rodriguez-Casero, Paul J Lockhart, Adeline Vanderver, Cas Simons, Susan Gibb, Simon Sadedin, Susan M White, John Christodoulou, Olga Skibina, Jonathan Ruddle, Tiong Y Tan, Richard J Leventer, John H Livingston, Miriam H Meisler
The lipid phosphatase gene FIG. 4 is responsible for Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4J, a peripheral neuropathy. We now describe four families with FIG. 4 variants and prominent abnormalities of CNS white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG. 4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG...
February 10, 2019: Human Mutation
Thierry Soussi, Bernard Leroy, Michal Devir, Shai Rosenberg
The 1000 genome project, the Exome Aggregation Consortium (ExAC) or the Genome Aggregation database (gnomAD) datasets, were developed to provide large-scale reference data of genetic variations for various populations to filter out common benign variants and identify rare variants of clinical importance based on their frequency in the human population. Using a TP53 repository of 80,000 cancer variants, as well as TP53 variants from multiple cancer genome projects, we have defined a set of certified oncogenic TP53 variants...
February 5, 2019: Human Mutation
Lulu Li, Bin Mao, Shan Li, Jifang Xiao, Han Wang, Jing Zhang, Xiuzhi Ren, Yanzhou Wang, Yiyang Wu, Yixuan Cao, Chaoxia Lu, Jingsong Gao, Yi You, Feiyue Zhao, Xingzhu Geng, Yaxiong Xiao, Chendan Jiang, Yuqian Ye, Tao Yang, Xiuli Zhao, Xue Zhang
Osteogenesis imperfecta (OI) is a rare hereditary skeletal dysplasia, characterized by recurrent fractures and bone deformity. This study presents a clinical characterization and mutation analysis of 668 patients, aiming to establish the mutation spectrum and to elucidate genotype-phenotype correlations in Chinese OI patients. We identified 274 sequence variants (230 in type I collagen encoding genes and 44 in non-collagen genes), including 102 novel variants, in 340 probands with a detection rate of 90%. Compared with 47 loss-of-function variants detected in COL1A1, neither nonsense nor frameshift variants were found in COL1A2 (P < 0...
February 4, 2019: Human Mutation
Raquel S Silva, Gavin Arno, Valentina Cipriani, Nikolas Pontikos, Sabine Defoort-Dhellemmes, Ambreen Kalhoro, Keren J Carss, F Lucy Raymond, Claire Marie Dhaenens, Hanne Jensen, Thomas Rosenberg, Veronica van Heyningen, Anthony T Moore, Bernard Puech, Andrew R Webster
The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 which overlaps the North Carolina Macular Dystrophy (NCMD) locus MCDR1. NCMD is a non-progressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA and two individuals from an additional family with a related developmental macular dystrophy...
February 2, 2019: Human Mutation
Xiaojin Li, Wei Zhang, Donghu Zhou, Tingxia Lv, Anjian Xu, Hejing Wang, Xinyan Zhao, Bei Zhang, Yanmeng Li, Siyu Jia, Yu Wang, Xiaoming Wang, Zhen Wu, Weijia Duan, Qianyi Wang, Yuemin Nan, Jia Shang, Wei Jiang, Yongpeng Chen, Sujun Zheng, Mei Liu, Liying Sun, Hong You, Jidong Jia, Xiaojuan Ou, Jian Huang
Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. Here, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12...
January 31, 2019: Human Mutation
Sarah Naessens, Julie De Zaeytijd, Delfien Syx, Roosmarijn E Vandenbroucke, Frédéric Smeets, Caroline Van Cauwenbergh, Bart P Leroy, Frank Peelman, Frauke Coppieters
Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N-terminal mutation. Haplotype reconstruction in three SFD families revealed that the identified c.113C > G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype. Functional consequences of the p...
January 22, 2019: Human Mutation
Kunwar Jung-Kc, Nastassja Himmelreich, Karina S Prestegård, Tie-Jun Sten Shi, Tanja Scherer, Ming Ying, Ana Jorge-Finnigan, Beat Thöny, Nenad Blau, Aurora Martinez
DNAJC12, a type III member of the HSP40/DNAJ family, has been identified as the specific co-chaperone of phenylalanine hydroxylase (PAH) and the other aromatic amino acid hydroxylases. DNAJ proteins work together with molecular chaperones of the HSP70-family to assist in proper folding and maintenance of intracellular stability of their clients. Autosomal recessive mutations in DNAJC12 were found to reduce PAH levels, leading to hyperphenylalaninemia (HPA) in patients without mutations in PAH. In this work we investigated the interaction of normal wild-type DNAJC12 with mutant PAH in cells expressing several PAH variants associated with HPA in humans, as well as in the Enu1/1 mouse model, homozygous for the V106A-Pah variant, which leads to severe protein instability, accelerated PAH degradation and mild HPA...
January 22, 2019: Human Mutation
Nicole Köger, Angela Brieger, Inga M Hinrichsen, Stefan Zeuzem, Guido Plotz
The human DNA repair gene MUTYH, whose mutational loss causes a colorectal polyposis and cancer predisposition, contains three alternative first exons. In order to analyze alternative transcription and the effect of genetic alterations found in humans, we established a cell-based minigene experimental model supporting transcription and splicing and thoroughly verified its functionality. We identified highly conserved promoter areas and inactivated them in the minigene, and also introduced six human variants...
January 17, 2019: Human Mutation
Brandon M D'Arcy, Jessa Blount, Aishwarya Prakash
Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20-30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management...
January 17, 2019: Human Mutation
Rasmus Scheller, Amelie Stein, Sofie V Nielsen, Frederikke I Marin, Anne-Marie Gerdes, Miriam Di Marco, Elena Papaleo, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Phenylketonuria (PKU) is a genetic disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine to neurotoxic levels. Here, we analyzed the cellular stability, localization and interaction with wild-type PAH of twenty selected PKU-linked PAH protein missense variants. Several were present at reduced levels in human cells, and the levels increased in the presence of proteasome inhibitor, indicating that the proteins are proteasome targets. We found that all the tested PAH variants retained their ability to associate with wild-type PAH, and none formed aggregates, suggesting that they are only mildly destabilized in structure...
January 16, 2019: Human Mutation
Soledad Ochoa, Elizabeth Martínez-Pérez, Diego Javier Zea, Miguel Angel Molina-Vila, Cristina Marino-Buslje
Malignant tumors originate from somatic mutations and other genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations present patterns of co-occurrence and mutual exclusivity that can influence prognosis and modify response to drugs, highlighting the need for multi targeted therapies. Studies in this area have generally focused in particular malignancies and considered whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects...
January 10, 2019: Human Mutation
Yan Li, Rachel Furhang, Amanda Ray, Todd Duncan, Joseph Soucy, Rashid Mahdi, Vijender Chaitankar, Linn Gieser, Eugenia Poliakov, Haohua Qian, Pinghu Liu, Lijin Dong, Igor B Rogozin, T Michael Redmond
Human RPE65 mutations cause a spectrum of retinal dystrophies that result in blindness. While RPE65 mutations have been almost invariably recessively inherited, a c.1430A>G (p.(D477G)) mutation has been reported to cause autosomal dominant retinitis pigmentosa (adRP). To study the pathogenesis of this human mutation, we have replicated the mutation in a knock-in (KI) mouse model using CRISPR/Cas9-mediated genome editing. Significantly, in contrast to human patients, heterozygous KI mice do not exhibit any phenotypes in visual function tests...
January 10, 2019: Human Mutation
Qingfeng Wang, Guannan Su, Xiao Tan, Jing Deng, Liping Du, Xinyue Huang, Meng Lv, Shenglan Yi, Shengping Hou, Aize Kijlstra, Peizeng Yang
Uveitis is an intraocular inflammatory disease which can lead to serious visual impairment. Genetic factors have been shown to be involved in its development. However, few databases have focused on the information of associations between single nucleotide polymorphisms (SNPs) and uveitis. To discover the exact genetic background of uveitis, we developed an SNP database specific for uveitis, 'UVEOGENE', which includes 370 genes and 918 SNPs covering 14 uveitis entities and 40 populations from 286 PubMed English-language papers...
January 7, 2019: Human Mutation
Xin-Xin Guo, Xiao-Huan Zou, Chong Wang, Xiang-Ping Yao, Hui-Zhen Su, Lu-Lu Lai, Hai-Ting Chen, Jing-Hui Lai, Yao-Bin Liu, Dong-Ping Chen, Yu-Chun Deng, Pan Lin, Hua-Song Lin, Bing-Cong Hong, Qing-Yang Yao, Xue-Jiao Chen, Dan-Qin Huang, Hong-Xia Fu, Ji-Dong Peng, Yan-Fang Niu, Yu-Ying Zhao, Xiao-Qun Zhu, Xiao-Pei Lu, Hai-Liang Lin, Yong-Kun Li, Chang-Yun Liu, Gen-Bin Huang, Ning Wang, Wan-Jin Chen
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0...
January 4, 2019: Human Mutation
Joana R Loureiro, Cláudia L Oliveira, Carolina Mota, Ana F Castro, Cristina Costa, José L Loureiro, Paula Coutinho, Sandra Martins, Jorge Sequeiros, Isabel Silveira
Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in non-pathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a non-coding region of DAB1...
December 26, 2018: Human Mutation
Min Sun, Chunlin Chen, Shengping Hou, Xue Li, Huan Wang, Jiaxing Zhou, Xi Chen, Pei Liu, Aize Kijlstra, Sen Lin, Jian Ye
Though many mutations have been identified to be associated with the occurrence of congenital cataract, pathogenic loci in some affected families are still unknown. Clinical data and genomic DNA were collected from a four-generation Chinese family. Candidate mutations were independently verified for cosegregation in the whole pedigree. Linkage analysis showed that the disease-causing mutation was located between 1p36.21 and 1p36.33. Analysis of the whole-exome sequencing data combined with linkage analysis identified a novel pathogenic variant (g...
December 25, 2018: Human Mutation
Rojeen Niazi, Elizabeth A Fanning, Christel Depienne, Mahdi Sarmady, Ahmad N Abou Tayoun
The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X-linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected although they pass on the pathogenic variant to each affected daughter. PCDH19-related disorder is known to cause early-onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life...
December 24, 2018: Human Mutation
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