Human Mutation最新文献

{"title":"Estimating the Prevalence of GNE Myopathy Using Population Genetic Databases","authors":"Alexa Derksen,&nbsp;Rachel Thompson,&nbsp;Madeeha Shaikh,&nbsp;Sally Spendiff,&nbsp;Theodore J. Perkins,&nbsp;Hanns Lochmüller","doi":"10.1155/2024/7377504","DOIUrl":"https://doi.org/10.1155/2024/7377504","url":null,"abstract":"<p>GNE myopathy (GNEM) is a rare autosomal recessive disorder characterized by progressive skeletal muscle wasting starting in early adulthood. The prevalence of GNEM is estimated to range between one and nine cases per million individuals, but the accuracy of these estimates is limited by underdiagnosis, misdiagnosis, and bias introduced by founder allele frequencies. As GNEM is a recessive disorder, unaffected carriers of single damaging variants can be expected to be found in the healthy population, providing an alternative method for estimating prevalence. We aim to estimate the prevalence of GNEM using allele frequencies obtained from healthy population genetic databases. We performed a review to establish a complete list of all known pathogenic GNEM variants from both literature and variant databases. We then developed standardized filtering steps using in silico tools to predict the pathogenicity of unreported <i>GNE</i> variants of uncertain clinical significance and validated our pathogenicity inferences using Mendelian Approach to Variant Effect pRedICtion built in Keras (MAVERICK) and AlphaMissense. We calculated conservative and liberal disease prevalence estimates using allele frequencies from the Genome Aggregation Database (gnomAD) population database by employing methodologies based on the assumptions of the Hardy–Weinberg Equilibrium. We additionally calculated estimates for disease prevalence removing the contribution of unique variant combinations that either do not cause myopathy in humans or result in embryonic lethality. We present the most comprehensive list of reported pathogenic <i>GNE</i> variants to date, together with additional variants predicted as pathogenic by in silico methods. We provide additional pathogenicity scores for these variants using new pathogenicity prediction tools and present a set of estimates for GNEM prevalence based on the different assumptions. Our most conservative estimate suggested a prevalence of 18.46 cases per million, while our most liberal estimate places the prevalence at 95.42 cases per million. When accounting for variant severity, this range drops to 11.00–87.68 cases per million. Our findings indicate that the true global prevalence of GNEM is greater than previous predictions underscoring that this condition is considerably more widespread than previously believed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7377504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099980","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}

{"title":"Genome Sequencing Unveils the Role of Copy Number Variants in Hearing Loss and Identifies Novel Deletions With Founder Effect in the DFNB1 Locus","authors":"Zibin Lin,&nbsp;Jiale Xiang,&nbsp;Xiangzhong Sun,&nbsp;Nana Song,&nbsp;Xiaozhou Liu,&nbsp;Qinming Cai,&nbsp;Jing Yang,&nbsp;Haodong Ye,&nbsp;Jiangfan Xu,&nbsp;Hongfu Zhang,&nbsp;Jiguang Peng,&nbsp;Yu Sun,&nbsp;Zhiyu Peng","doi":"10.1155/2024/9517114","DOIUrl":"https://doi.org/10.1155/2024/9517114","url":null,"abstract":"<p>Sensorineural hearing loss is a prevalent disorder with significant genetic involvement, which is often challenging to diagnose due to genetic heterogeneity. Exome sequencing (ES) has been a standard diagnostic tool for sensorineural hearing loss, but its limitations in detecting copy number variants (CNVs) and intronic variants have prompted the exploration of genome sequencing (GS) for improved diagnostic yield. We conducted GS on 46 hearing loss families with previously negative ES results and an additional cohort of 36 patients with a monoallelic pathogenic variant in <i>GJB2</i> (the most common deafness gene). Additionally, the impact of a previously unrecognized novel 125-kb deletion in the DFNB1 locus on <i>GJB2</i> expression was assessed using quantitative polymerase chain reaction (qPCR), and haplotype analysis was performed to characterize the deletion. GS diagnosed eight cases (17%, 8/46) in the ES-negative cohort, primarily attributed to CNVs (6/8). Notably, a previously unrecognized 125 kb deletion in the DFNB1 region was identified, affecting <i>GJB2</i> expression and characterizing it as a founder effect in East Asian. In 47 patients with a monoallelic <i>GJB2</i> variant, 15% (95% CI, 7.4%–28%) were diagnosed with DFNB1 deletions. Analysis of the gnomAD database revealed the prevalence and ethnic diversity of DFNB1 deletions, with the novel 125 kb deletion emerging as a prominent pathogenic variant in East Asian, non-Finnish European, and admixed American populations. Our study highlights the utility of GS in diagnosing sensorineural hearing loss. The identification of DFNB1 deletions underscores their significant contribution to hearing loss etiology, advocating for their inclusion in routine diagnostic testing. We propose GS as a primary genetic testing approach for patients with hearing loss, offering comprehensive genomic analysis and the potential for improved diagnostic accuracy.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9517114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141966985","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}

{"title":"Novel Pathogenic Variants in POLR3K Cause POLR3-Related Leukodystrophy","authors":"Stefanie Perrier,&nbsp;Julia Macintosh,&nbsp;Agata D. Misiaszek,&nbsp;Gabrielle Lambert,&nbsp;Kether Guerrero,&nbsp;Luan T. Tran,&nbsp;Christoph W. Müller,&nbsp;Tomi Pastinen,&nbsp;Gustavo H. B. Maegawa,&nbsp;Isabelle Thiffault,&nbsp;Geneviève Bernard","doi":"10.1155/2024/8807171","DOIUrl":"https://doi.org/10.1155/2024/8807171","url":null,"abstract":"<p>POLR3-related hypomyelinating leukodystrophy (POLR3-HLD) is a rare inherited neurological disorder caused by biallelic pathogenic variants in specific genes encoding subunits of RNA polymerase III (Pol III). Here, we report the third patient worldwide with pathogenic variants in <i>POLR3K</i> and clinical features consistent with POLR3-HLD. The female patient presented with mild intellectual and behavioural disturbances in childhood, as well as growth delay, with brain MRI revealing diffuse hypomyelination and a pattern consistent with POLR3-HLD. In adolescence, she manifested minor motor dysfunction. Next-generation sequencing revealed a paternally inherited missense variant in <i>POLR3K</i> (c.322G&gt;T; p.D108Y) and a maternally inherited large deletion, spanning approximately 17.8 kb from chr16:30,362-48,162. The missense variant is located at the C-terminus position of the protein and is predicted to impair residue interactions and cause steric interference in enzyme conformational changes. The large deletion encompasses the third and last exon of <i>POLR3K</i>, leading to a likely amorphic truncated protein product lacking the final 42 amino acids from the total 108 amino acid–length protein. Studies of RNA-level expression showed a significant reduction in the levels of <i>POLR3K</i> RNA in the patient compared to the control. In considering whether the transcriptional function of Pol III was affected, the expression of several Pol III-transcribed RNAs was measured, where the levels of several distinct tRNAs were significantly reduced in the patient while the expression of other RNA transcripts was not decreased, suggesting that Pol III retains partial function. This study provides further evidence for the association of pathogenic variants in <i>POLR3K</i> with POLR3-HLD, expanding the spectrum of pathogenic variants in genes encoding for Pol III subunits associated with this disease.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8807171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968403","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}

{"title":"Application of Targeted Y-Chromosomal Capture Enrichment to Increase the Resolution of Native American Haplogroup Q","authors":"Zehra Köksal,&nbsp;Claus Børsting,&nbsp;Graciela Bailliet,&nbsp;Germán Burgos,&nbsp;Elizeu Carvalho,&nbsp;Andrea Casas-Vargas,&nbsp;Adriana Castillo,&nbsp;Marilia Brito Gomes,&nbsp;Beatriz Martínez,&nbsp;Humberto Ossa,&nbsp;María Laura Parolin,&nbsp;Alfredo Quiroz,&nbsp;Ulises Toscanini,&nbsp;William Usaquén,&nbsp;Irina F. Velázquez,&nbsp;Carlos Vullo,&nbsp;Leonor Gusmão,&nbsp;Vania Pereira","doi":"10.1155/2024/3046495","DOIUrl":"https://doi.org/10.1155/2024/3046495","url":null,"abstract":"<p>Y-chromosomal haplogroups and the Y-SNPs defining them are relevant for the exploration of male lineages, inference of paternal ancestry, and reconstruction of migration pathways, to name a few. Currently, over 300,000 Y-SNPs have been reported, defining 20 main haplogroups. However, ascertainment bias in the investigations has led to some haplogroups being overlooked, which hinders a representative depiction of certain populations and their migration events. For migration pattern analyses of the first settlers of the Americas, the Native American main founding lineage Q-M3 needs to be further investigated to allow clear genetic differentiation of individuals of different ethnogeographic origins. To increase the resolution within this haplogroup, a total of 7.45 Mb of the Y chromosome of 59 admixed South Americans of haplogroup Q was targeted for sequencing using hybridization capture enrichment. Data were combined with 218 publicly available sequences of Central and South Americans of haplogroup Q. After rigorous data processing, variants not meeting the quality criteria were excluded and 4128 reliable Y-SNPs were reported. A total of 2224 Y-SNPs had previously unknown positions in the phylogenetic tree, and 1291 of these are novel. The phylogenetic relationships between the Y-SNPs were established using the software SNPtotree in order to report a redesigned phylogenetic tree containing 300 branches, defined by 3400 Y-SNPs. The new tree introduces 117 previously undescribed branches and is the most comprehensive phylogenetic tree of the Native American haplogroup Q lineages to date. The 214 sequences were assigned to 135 different low- to high-resolution branches, while in the previous phylogenetic tree, only 195 sequences could be sorted into 14 low-resolution branches with the same quality criteria. The improved genetic differentiation of subhaplogroup Q-M3 has a great potential to resolve migration patterns of Native Americans.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3046495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141967119","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}

{"title":"Homozygous HOXC13 Variant Causes Pure Hair and Nail Ectodermal Dysplasia via Reduction in Protein Stability","authors":"Virginia Clowes,&nbsp;Xiaolun Ma,&nbsp;Hannah Maude,&nbsp;Catherine Dennis,&nbsp;Qing Gao,&nbsp;Geraldine Quinn,&nbsp;Edel A. O’Toole,&nbsp;Kapila Batta,&nbsp;Inês Cebola,&nbsp;Wei Cui","doi":"10.1155/2024/6420246","DOIUrl":"https://doi.org/10.1155/2024/6420246","url":null,"abstract":"<p>Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder characterized by reduced or absent hair and dystrophic nails. PHNED is caused by pathogenic variants in genes involved in hair and nail development, including <i>HOXC13</i>. Previously reported biallelic <i>HOXC13</i> pathogenic variants led to PHNED by either disrupting protein expression through nonsense-mediated decay or altering the DNA-binding affinity of the homeobox domain of HOXC13. Here, we report a case of <i>HOXC13</i>-related PHNED with a rare homozygous variant, c.931C&gt;T, p.Arg311Trp. Similarly to previously reported missense variants, p.Arg311Trp resides in the homeobox domain of HOXC13 and was assumed to lead to the decreased transcriptional activity of target genes. However, in contrast with previously reported variants, <i>in vitro</i> overexpression assays revealed that the p.Arg311Trp variant decreases HOXC13 protein stability, which is corroborated by a series of <i>in silico</i> predictions. Computational models further suggest that p.Arg311Trp results in a structural rearrangement with loss of interhelical connection between Arg311 in <i>α</i>-helix 3 and Glu276 in <i>α</i>-helix 1. Altogether, our results suggest a novel molecular mechanism causative of PHNED, whereby biallelic pathogenic variants in <i>HOXC13</i> may result in decreased protein stability and consequently decreased transcriptional activity of target genes essential for hair and nail development.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6420246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141487760","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}

{"title":"Pi*S and Pi*Z Alleles of SERPINA1 Gene Are Associated With Specific Variants of a BRD4-Independent Enhancer","authors":"Ainhoa Escuela-Escobar,&nbsp;Esther Herrera-Luis,&nbsp;Elena Martín-González,&nbsp;José María Hernández-Pérez,&nbsp;Mario A. González Carracedo,&nbsp;José Antonio Pérez Pérez","doi":"10.1155/2024/6472805","DOIUrl":"https://doi.org/10.1155/2024/6472805","url":null,"abstract":"<p>Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by specific variants in the <i>SERPINA1</i> gene, which encodes AAT. The most common disease-associated <i>SERPINA1</i> variants are <i>Pi</i> ∗ <i>S</i> and <i>Pi</i> ∗ <i>Z</i> alleles, which cause moderate and severe AATD, respectively. Recent studies have reported the presence of a possible regulator of <i>SERPINA</i> gene cluster expression (LOC126862032), which is suggested to act as a BRD4-Independent Enhancer (<i>SERPINA</i>-BIE). This study is aimed at characterizing the <i>SERPINA</i>-BIE locus and assessing possible associations with <i>SERPINA1</i> AATD-related alleles. For this purpose, <i>SERPINA</i>-BIE was PCR genotyped from 917 samples, including 452 asthmatic patients, and 465 newborns. Nine <i>SERPINA</i>-BIE alleles were sequenced, revealing a specific combination of 56-bp sequence types, and each <i>SERPINA</i>-BIE allele has a unique total number of CpG sites. Statistical analyses revealed an association between the <i>Pi</i> ∗ <i>Z</i> allele of the <i>SERPINA1</i> gene and the <i>SERPINA</i>-BIE allele 13 (<i>p</i> value = 5.51 × 10⁻¹⁰), as well as between <i>Pi</i> ∗ <i>S</i> and <i>SERPINA</i>-BIE allele 14 (<i>p</i> value = 8.95 × 10⁻¹⁵). However, AAT levels were not associated with <i>SERPINA</i>-BIE alleles when models were corrected by <i>SERPINA1</i> genotypes. This study could contribute to a better understanding of the regulation of the <i>SERPINA1</i> gene expression, and its role in AATD.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6472805","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141488429","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}

{"title":"Biallelic Recessive Mutations in TLE6 and NLRP5 Cause Female Infertility Characterized by Human Early Embryonic Arrest","authors":"Ruiqi Li,&nbsp;Mei Mei,&nbsp;Ling Zhou,&nbsp;Haijing Zhao,&nbsp;Min Yang,&nbsp;Yingshi Li,&nbsp;Xiaoli Chen,&nbsp;Wenjun Wang,&nbsp;Ping Yuan","doi":"10.1155/2024/9278518","DOIUrl":"https://doi.org/10.1155/2024/9278518","url":null,"abstract":"<div>\u0000 <p>Preimplantation embryonic developmental arrest (EDA) is a common cause of unexplained female infertility. Genetic factors are believed to be one of the primary causes contributing to EDA. In this study, we identify four novel compound heterozygous mutations in <i>TLE6</i> and <i>NLRP5</i>, in two infertile female patients experiencing recurrent EDA, using whole-exome sequencing. Functional analysis revealed that the two splicing mutations in <i>TLE6</i> (c.541+2dupT) and <i>NLRP5</i> (c.2957+4A&gt;G) resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. <i>In vitro</i> experiments further validated that a missense mutation in <i>NLRP5</i> led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells. Immunofluorescence analysis confirmed the decay of the expression of TLE6 protein. Additionally, RNA sequencing results revealed significantly higher expression levels of some maternal genes in mutated embryos with <i>TLE6</i> mutations, possibly suggesting the disrupted clearance of maternal mRNA and the failure of embryo genome activation. These results highlight the role of biallelic recessive effects associated with <i>TLE6</i> and <i>NLRP5</i> variants in embryonic development, thereby widening the scope of the genetic landscape.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9278518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439610","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}

{"title":"Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments","authors":"Bianca Zardetto,&nbsp;Willeke van Roon-Mom,&nbsp;Annemieke Aartsma-Rus,&nbsp;Marlen C. Lauffer","doi":"10.1155/2024/9933129","DOIUrl":"https://doi.org/10.1155/2024/9933129","url":null,"abstract":"<div>\u0000 <p>Neurodevelopmental disorders (NDDs) of genetic origin are a group of early-onset neurological diseases with highly heterogeneous etiology and a symptomatic spectrum that includes intellectual disability, autism spectrum disorder, and learning and language disorders. One group of rare NDDs is associated with dysregulation of the KMT2 protein family. Members of this family share a common methyl transferase function and are involved in the etiology of rare haploinsufficiency disorders. For each of the <i>KMT2</i> genes, at least one distinct disorder has been reported, yet clinical manifestations often overlap for multiple of these individually very rare disorders. Clinical care is currently focused on the management of symptoms with no targeted treatments available, illustrating a high unmet medical need and the urgency of developing disease-modifying therapeutic strategies. Antisense oligonucleotides (ASOs) are one option to treat some of these rare genetic disorders. ASOs are RNA-based treatments that can be employed to modulate gene expression through various mechanisms. In this work, we discuss the phenotypic features across the <i>KMT2</i>-associated NDDs and which ASO approaches are most suited for the treatment of each associated disorder. We hereby address variant-specific strategies as well as options applicable to larger groups of patients.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9933129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246167","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}

{"title":"Characterization and Engineered U1 snRNA Rescue of Splicing Variants in a Turkish Neurodevelopmental Disease Cohort","authors":"Ece Sönmezler,&nbsp;Cristiana Stuani,&nbsp;Semra Hız Kurul,&nbsp;Serdal Güngör,&nbsp;Emanuele Buratti,&nbsp;Yavuz Oktay","doi":"10.1155/2024/7760556","DOIUrl":"https://doi.org/10.1155/2024/7760556","url":null,"abstract":"<div>\u0000 <p>Although they are rare in the population, rare neurodevelopmental disorders (RNDDs) constitute a significant portion of all rare diseases. While advancements in sequencing technologies led to improvements in diagnosing and managing rare neurodevelopmental diseases, accurate pathogenicity classification of the identified variants is still challenging. Sequence variants altering pre-mRNA splicing make up a significant part of pathogenic variants. Despite advances in the <i>in silico</i> prediction tools, noncanonical splice site variants are one of the groups of variants that pose a challenge in their clinical interpretation. In this study, we analyzed the effects of seven splicing variants we had previously proposed as disease-causing and demonstrated that all but one of the seven variants had a strong or moderate effect on splicing, as assessed by a minigene assay. Next, applying U1 snRNAs engineered for different splicing variants in the corresponding genes and expressed with minigene plasmids in HeLa cells provided a partial correction in four of the studied genes to varying degrees. Findings from our study highlight the importance of in vitro minigene-based assays for the reclassification of putative splice-altering variants of uncertain significance and the therapeutic potential of modified U1 snRNAs in RNDDs.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7760556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246005","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}

{"title":"Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes—ENG and ACVRL1","authors":"Desiree DeMille,&nbsp;Jamie McDonald,&nbsp;Carmelo Bernabeu,&nbsp;Hilary Racher,&nbsp;Carla Olivieri,&nbsp;Claudia Cantarini,&nbsp;Anna Sbalchiero,&nbsp;Bryony A. Thompson,&nbsp;Luca Jovine,&nbsp;Claire L. Shovlin,&nbsp;Sophie Dupuis-Girod,&nbsp;Gaetan Lesca,&nbsp;Maud Tusseau,&nbsp;Arupa Ganguly,&nbsp;Raj S. Kasthuri,&nbsp;Jaime Jessen,&nbsp;Maarten P. G. Massink,&nbsp;Shoji Ichikawa,&nbsp;Pinar Bayrak-Toydemir","doi":"10.1155/2024/3043736","DOIUrl":"10.1155/2024/3043736","url":null,"abstract":"<div>\u0000 <p>The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the <i>ENG</i> and <i>ACVRL1</i> genes. Eight of the original ACMG/AMP rules were determined to not be applicable for <i>ENG</i>- or <i>ACVRL1</i>-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.</p>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3043736","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141125031","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}