Human Mutation最新文献_第9页

KBTBD13 is a novel cardiomyopathy gene. KBTBD13是一种新的心肌病基因。

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24499

Josine M de Winter, Karlijn Bouman, Joshua Strom, Mei Methawasin, Jan D H Jongbloed, Wilma van der Roest, Jan van Wijngaarden, Janneke Timmermans, Robin Nijveldt, Frederik van den Heuvel, Erik-Jan Kamsteeg, Baziel G van Engelen, Ricardo Galli, Sylvia J P Bogaards, Reinier A Boon, Robbert J van der Pijl, Henk Granzier, Bobby Koeleman, Ahmad S Amin, Jolanda van der Velden, J Peter van Tintelen, Maarten P van den Berg, Karin Y van Spaendonck-Zwarts, Nicol C Voermans, Coen A C Ottenheijm

{"title":"KBTBD13 is a novel cardiomyopathy gene.","authors":"Josine M de Winter, Karlijn Bouman, Joshua Strom, Mei Methawasin, Jan D H Jongbloed, Wilma van der Roest, Jan van Wijngaarden, Janneke Timmermans, Robin Nijveldt, Frederik van den Heuvel, Erik-Jan Kamsteeg, Baziel G van Engelen, Ricardo Galli, Sylvia J P Bogaards, Reinier A Boon, Robbert J van der Pijl, Henk Granzier, Bobby Koeleman, Ahmad S Amin, Jolanda van der Velden, J Peter van Tintelen, Maarten P van den Berg, Karin Y van Spaendonck-Zwarts, Nicol C Voermans, Coen A C Ottenheijm","doi":"10.1002/humu.24499","DOIUrl":"https://doi.org/10.1002/humu.24499","url":null,"abstract":"KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1860-1865"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/62/ba/HUMU-43-1860.PMC10100581.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9297885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutation update for the ACTN2 gene. ACTN2基因的突变更新。

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24470

Johanna Ranta-Aho, Montse Olive, Marie Vandroux, Giorgia Roticiani, Cristina Dominguez, Mridul Johari, Annalaura Torella, Johann Böhm, Janina Turon, Vincenzo Nigro, Peter Hackman, Jocelyn Laporte, Bjarne Udd, Marco Savarese

{"title":"Mutation update for the ACTN2 gene.","authors":"Johanna Ranta-Aho, Montse Olive, Marie Vandroux, Giorgia Roticiani, Cristina Dominguez, Mridul Johari, Annalaura Torella, Johann Böhm, Janina Turon, Vincenzo Nigro, Peter Hackman, Jocelyn Laporte, Bjarne Udd, Marco Savarese","doi":"10.1002/humu.24470","DOIUrl":"https://doi.org/10.1002/humu.24470","url":null,"abstract":"ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. The protein, located in the sarcomere Z-disk, functions as a link between the anti-parallel actin filaments. This important structural protein also binds N-terminal titins, and thus contributes to sarcomere stability. Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease. Recently, however, ACTN2 mutations have been associated with novel congenital and distal myopathy. Previously reported variants are in varying locations across the gene, but the potential clustering effect of pathogenic locations is not clearly understood. Further, the genotype-phenotype correlations of these variants remain unclear. Here we review the previously reported ACTN2-related molecular and clinical findings and present an additional variant, c.1840-2A>T, that further expands the mutation and phenotypic spectrum. Our results show a growing body of clinical, genetic, and functional evidence, which underlines the central role of ACTN2 in the muscle tissue and myopathy. However, limited segregation and functional data are available to support the pathogenicity of most previously reported missense variants and clear-cut genotype-phenotype correlations are currently only demonstrated for some ACTN2-related myopathies.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1745-1756"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9655471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals. 致病性c.1171A>G (p.Arg391Gly)和c.2359G>A (p.Val787Ile) ABCC6变异在部分个体中显示不完全外显性，导致弹性假黄瘤。

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24498

Flora Szeri, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, Sharon F Terry, Federica Boraldi, Jouni Uitto, Koen van de Wetering, Ludovic Martin, Daniela Quaglino, Olivier M Vanakker, Kalman Tory, Tamas Aranyi

{"title":"The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.","authors":"Flora Szeri, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, Sharon F Terry, Federica Boraldi, Jouni Uitto, Koen van de Wetering, Ludovic Martin, Daniela Quaglino, Olivier M Vanakker, Kalman Tory, Tamas Aranyi","doi":"10.1002/humu.24498","DOIUrl":"https://doi.org/10.1002/humu.24498","url":null,"abstract":"ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1872-1881"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9297864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association. 原发性高血尿酸III型的HOGA1基因致病变异:致病序列变异谱和表型关联

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24490

Aiysha Abid, Ali Raza, Tahir Aziz, Shagufta Khaliq

{"title":"HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association.","authors":"Aiysha Abid, Ali Raza, Tahir Aziz, Shagufta Khaliq","doi":"10.1002/humu.24490","DOIUrl":"https://doi.org/10.1002/humu.24490","url":null,"abstract":"Primary hyperoxalurias (PH) are a group of rare heterogeneous disorders characterized by deficiencies in glyoxylate metabolism. To date, three genes have been identified to cause three types of PH (I, II, and III). The HOGA1 gene caused type III in around 10% of the PH cases. Disease-associated pathogenic variants have been reported from several populations and a comprehensive spectrum of these mutations and genotype-phenotype correlation has never been presented. In this study, we describe new cases of the HOGA1 gene pathogenic variants identified in our population. We report the first case of ESKD with successful kidney transplantation with 5 years of follow-up. Furthermore, a comprehensive overview of PH type III associated HOGA1 gene variants was carried out. Compiling the data from the literature, we reviewed 57 distinct HOGA1 gene pathogenic variants in 175 patients worldwide. The majority of reported variants are missense variants that predicted a loss of function mechanism as the underlying pathology. There has been evidence of the presence of founder mutations in several populations like Europeans, Ashkenazi Jews, Arab, and Chinese populations. No significant genotype-phenotype correlation was identified concerning the ages of onset of the disease and biochemical and metabolic parameters. Nephrocalcinosis was rare in patients with disease-associated variants. Most of the patients were presented with urolithiasis early in life; only five cases reported disease progression after the second decade of life. The establishment of impairment of renal function in 8% of all the reported cases makes this type a relatively severe form of primary hyperoxaluria, not a benign etiology as suggested previously.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1757-1779"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10813822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Isolated aneurysmal disease as an underestimated finding in individuals with JAG1 pathogenic variants. 孤立的动脉瘤疾病是JAG1致病性变异个体中被低估的发现。

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24433

Jotte Rodrigues Bento, Alice Krebsová, Ilse Van Gucht, Irene Valdivia Callejon, An Van Berendoncks, Pavel Votypka, Ilse Luyckx, Petra Peldova, Steven Laga, Marek Havelka, Lut Van Laer, Pavel Trunecka, Nele Boeckx, Aline Verstraeten, Milan Macek, Josephina A N Meester, Bart Loeys

引用次数: 1

ENPP1 deficiency: A clinical update on the relevance of individual variants using a locus-specific patient database. ENPP1缺乏症:使用基因座特异性患者数据库的个体变异相关性的临床更新。

IF 3.9 2区医学

Human Mutation Pub Date : 2022-12-01 DOI: 10.1002/humu.24477

Stephanie A Mercurio, Lauren M Chunn, Gus Khursigara, Catherine Nester, Kathleen Wray, Ulrike Botschen, Mark J Kiel, Frank Rutsch, Carlos R Ferreira

{"title":"ENPP1 deficiency: A clinical update on the relevance of individual variants using a locus-specific patient database.","authors":"Stephanie A Mercurio, Lauren M Chunn, Gus Khursigara, Catherine Nester, Kathleen Wray, Ulrike Botschen, Mark J Kiel, Frank Rutsch, Carlos R Ferreira","doi":"10.1002/humu.24477","DOIUrl":"https://doi.org/10.1002/humu.24477","url":null,"abstract":"Loss-of-function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation, and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality in infants, autosomal recessive hypophosphatemic rickets type 2 (ARHR2) in children, and joint pain, osteomalacia and enthesopathies in adults. Recent research continues to add to the growing clinical presentation profile as well as expanding the role of ENPP1 itself. Here we review the current knowledge on the spectrum of clinical and genetic findings of ENPP1 Deficiency reported in patients diagnosed with GACI or ARHR2 phenotypes using a comprehensive database of known ENPP1 variants with associated clinical data. A total of 108 genotypes were identified from 154 patients. Of the 109 ENPP1 variants reviewed, 72.5% were demonstrably disease-causing, a threefold increase in pathogenic/likely pathogenic variants over other databases. There is substantial heterogeneity in disease severity, even among patients with the same variant. The approach to creating a continuously curated database of ENPP1 variants accessible to clinicians is necessary to increase the diagnostic yield of clinical genetic testing and accelerate diagnosis of ENPP1 Deficiency.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"1673-1705"},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10557994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Variant effect on splicing regulatory elements, branchpoint usage, and pseudoexonization: Strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars 剪接调控元件、分支点使用和假外显子化的变异效应:以遗传癌症基因为例增强生物信息学预测的策略

IF 3.9 2区医学

Human Mutation Pub Date : 2022-11-30 DOI: 10.1002/humu.24500

Daffodil Canson, Dylan Glubb, Amanda B. Spurdle

引用次数: 1

Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality PTPN11 (HGNC:9644)变异的种系选择对努南综合征的高出生率和散发的癌症变异的传播造成胎儿异常做出了主要贡献

IF 3.9 2区医学

Human Mutation Pub Date : 2022-11-09 DOI: 10.1002/humu.24493

Jordan Eboreime, Soo-Kyung Choi, Song-Ro Yoon, Anastasiia Sadybekov, Vsevolod Katritch, Peter Calabrese, Norman Arnheim

{"title":"Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality","authors":"Jordan Eboreime, Soo-Kyung Choi, Song-Ro Yoon, Anastasiia Sadybekov, Vsevolod Katritch, Peter Calabrese, Norman Arnheim","doi":"10.1002/humu.24493","DOIUrl":"10.1002/humu.24493","url":null,"abstract":"Some spontaneous germline gain-of-function mutations promote spermatogonial stem cell clonal expansion and disproportionate variant sperm production leading to unexpectedly high transmission rates for some human genetic conditions. To measure the frequency and spatial distribution of de novo mutations we divided three testes into 192 pieces each and used error-corrected deep-sequencing on each piece. We focused on PTPN11 (HGNC:9644) Exon 3 that contains 30 different PTPN11 Noonan syndrome (NS) mutation sites. We found 14 of these variants formed clusters among the testes; one testis had 11 different variant clusters. The mutation frequencies of these different clusters were not correlated with their case-recurrence rates nor were case recurrence rates of PTPN11 variants correlated with their tyrosine phosphatase levels thereby confusing PTPN11's role in germline clonal expansion. Six of the PTPN11 exon 3 de novo variants associated with somatic mutation-induced sporadic cancers (but not NS) also formed testis clusters. Further, three of these six variants were observed among fetuses that underwent prenatal ultrasound screening for NS-like features. Mathematical modeling showed that germline selection can explain both the mutation clusters and the high incidence of NS (1/1000–1/2500).","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2205-2221"},"PeriodicalIF":3.9,"publicationDate":"2022-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9351049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu-mediated copy number variations at the PRPF31 locus 视网膜色素变性患者PRPF31基因的综合分析:四个新的铝介导的PRPF31位点拷贝数变异

IF 3.9 2区医学

Human Mutation Pub Date : 2022-11-01 DOI: 10.1002/humu.24494

Zhixuan Chen, Jieqiong Chen, Min Gao, Yang Liu, Yidong Wu, Yafang Wang, Yuanyuan Gong, Suqin Yu, Wenjia Liu, Xiaoling Wan, Xiaodong Sun

{"title":"Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu-mediated copy number variations at the PRPF31 locus","authors":"Zhixuan Chen, Jieqiong Chen, Min Gao, Yang Liu, Yidong Wu, Yafang Wang, Yuanyuan Gong, Suqin Yu, Wenjia Liu, Xiaoling Wan, Xiaodong Sun","doi":"10.1002/humu.24494","DOIUrl":"10.1002/humu.24494","url":null,"abstract":"Retinitis pigmentosa (RP) is a monogenic disease characterized by irreversible degeneration of the retina. PRPF31, the second most common causative gene of autosomal dominant RP, frequently harbors copy number variations (CNVs), but the underlying mechanism is unclear. In this study, we summarized the phenotypic and genotypic characteristics of 18 RP families (F01−F18) with variants in PRPF31. The prevalence of PRPF31 variants in our cohort of Chinese RP families was 1.7% (18/1024). Seventeen different variants in PRPF31 were detected, including eight novel variants. Notably, four novel CNVs encompassing PRPF31, with a proportion of 22.2% (4/18), were validated to harbor gross deletions involving Alu/Alu-mediated rearrangements (AAMRs) in the same orientation. Among a total of 12 CNVs of PRPF31 with breakpoints mapped on nucleotide-resolution, 10 variants (83.3%) were presumably mediated by Alu elements. Furthermore, we described the correlation between the genotypes and phenotypes in PRPF31-related RP. Our findings expand the mutational spectrum of the PRPF31 gene and provide strong evidence that Alu elements of PRPF31 probably contribute to the susceptibility to genomic rearrangement in this locus.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2279-2294"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9137403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV 新的临床和分子证据将ARSG突变与Usher综合征IV型联系起来

IF 3.9 2区医学

Human Mutation Pub Date : 2022-11-01 DOI: 10.1002/humu.24496

Virginie G. Peter, Mathieu Quinodoz, Silvia Sadio, Sebastian Held, Márcia Rodrigues, Marta Soares, Ana Berta Sousa, Luisa Coutinho Santos, Markus Damme, Carlo Rivolta

引用次数: 0