Human Mutation最新文献

{"title":"Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs ∗41) by Whole-Exome Sequencing in Patients with Crohn’s Disease","authors":"Jintong Chen,&nbsp;Yanni Huang,&nbsp;Huaning Chen,&nbsp;Qinyu Yang,&nbsp;Weiwei Zheng,&nbsp;Yanjun Lin,&nbsp;Mengli Xue,&nbsp;Chengdang Wang","doi":"10.1155/2024/5573272","DOIUrl":"10.1155/2024/5573272","url":null,"abstract":"<p><i>NLRP12</i> encodes the nucleotide-binding leucine-rich repeat-containing receptor 12 protein and has been linked to familial cold autoinflammatory syndrome 2 (FCAS2). Previous studies have reported that NLRP12 protein can dampen inflammatory responses in DSS-induced mice colitis. To date, only four alterations in the <i>NLRP12</i> gene have been associated with Crohn’s disease (CD). Here, we reported a novel heterozygous <i>NLRP12</i> frameshift mutation (c.2188dupG, p.Val730Glyfs ^∗41) identified by whole-exome sequencing in the proband with CD. The Sanger sequencing confirmed that his sister and father also carried this <i>NLRP12</i> mutation, which cosegregated well with the CD phenotype. In silico analysis predicted this mutation to be disease-causing. Patients heterozygous for this mutation exhibited decreased NLRP12 protein levels in the peripheral blood and colon. Functional assays showed that mutant <i>NLRP12</i> plasmid-transfected HEK293T cells exhibited significantly lower <i>NLRP12</i> mRNA and protein levels than wild-type plasmid-transfected cells. The nonsense-mediated decay inhibitor NMDI14 significantly increased <i>NLRP12</i> mRNA and protein levels in mutant plasmid-transfected cells. Overall, our results demonstrated that this heterozygous <i>NLRP12</i> mutation (c.2188dupG) resulted in decreased NLRP12 expression, which might contribute to the mechanism underlying CD.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140435450","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}

{"title":"COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient","authors":"Xue-Yuan Zhang,&nbsp;Jing Zhang,&nbsp;Yi Lu","doi":"10.1155/2024/9857442","DOIUrl":"10.1155/2024/9857442","url":null,"abstract":"<p>Here, we present a Han Chinese pediatric girl highly suspected of congenial disorder of glycosylation type IIL (CDG2L; OMIM#614576). Her clinical symptoms include transferase abnormal, liver cirrhosis, hemogram, coagulopathy, growth retardation, intellectual disability, frequent infections, and enamel hypoplasia. Trio-genome sequencing identified in <i>COG6</i> a paternal variant c.1672C&gt;T (p.Gln558Ter) and a maternal variant c.153+392A&gt;G (p.?). Reverse transcription-polymerase chain reaction (RT-PCR) using mRNA isolated from peripheral blood confirmed the pathogenicity of both variants. The paternal variant resulted in nonsense-mediated mRNA decay. The maternal variant generated two aberrant <i>COG6</i> transcripts with 154 bp overlap and was predicted to result in a frameshift at the same position, leading to generation of a premature termination codon. They might result in synthesis of a truncated form of COG6. Thus, the patient was genetically diagnosed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139783222","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}

{"title":"The Missing Piece of the Puzzle: Unveiling the Role of PTPN11 Gene in Multiple Osteochondromas in a Large Cohort Study","authors":"Artem Borovikov,&nbsp;Nailya Galeeva,&nbsp;Andrey Marakhonov,&nbsp;Aysylu Murtazina,&nbsp;Varvara Kadnikova,&nbsp;Kseniya Davydenko,&nbsp;Anna Orlova,&nbsp;Peter Sparber,&nbsp;Tatiana Markova,&nbsp;Maria Orlova,&nbsp;Darya Osipova,&nbsp;Tatyana Nagornova,&nbsp;Natalia Semenova,&nbsp;Olga Levchenko,&nbsp;Alexandra Filatova,&nbsp;Margarita Sharova,&nbsp;Peter Vasiluev,&nbsp;Ilya Kanivets,&nbsp;Denis Pyankov,&nbsp;Artem Sharkov,&nbsp;Vasilisa Udalova,&nbsp;Vladimir Kenis,&nbsp;Natalia Nikitina,&nbsp;Maria Sumina,&nbsp;Konstantin Zherdev,&nbsp;Aleksandr Petel′guzov,&nbsp;Oleg Chelpachenko,&nbsp;Pavel Zubkov,&nbsp;Ivan Dan,&nbsp;Andrey Snetkov,&nbsp;Alexandra Akinshina,&nbsp;Yury Buklemishev,&nbsp;Oxana Ryzhkova,&nbsp;Vyacheslav Tabakov,&nbsp;Ekaterina Zakharova,&nbsp;Sergey Korostelev,&nbsp;Rena Zinchenko,&nbsp;Mikhail Skoblov,&nbsp;Alexander Polyakov,&nbsp;Elena Dadali,&nbsp;Sergey Kutsev,&nbsp;Olga Shchagina","doi":"10.1155/2024/8849348","DOIUrl":"10.1155/2024/8849348","url":null,"abstract":"<p>This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the <i>EXT1</i> or <i>EXT2</i> genes, with DNA diagnostic yield ranging from 78 to 95%. The <i>PTPN11</i> gene, which is causative for MC, was not previously investigated as a gene candidate for MO. In this study, we detected a total of 177 unique single nucleotide and copy number variants in three genes across 220 probands, consisting of 80 previously reported and 97 novel variants. Specifically, we identified five cases with OCs and no ECs as well as four cases with MC carrying LoF variants in the <i>PTPN11</i> gene and two additional cases with ECs harboring variants in the <i>EXT1/2</i> genes. These findings suggest a potential overlap between the MO and MC both phenotypically and genetically. These findings highlight the importance of expanding genetic testing beyond the <i>EXT1</i> and <i>EXT2</i> genes in MO cases, as other genes such as <i>PTPN11</i> may also be causative. This can improve the accuracy of diagnosis and treatment for individuals with MO and MC. It is essential to determine whether MO and MC represent distinct diseases or if they encompass a broader clinical spectrum.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139843644","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}

{"title":"Characterisation of a LINE-1 Insertion in the RP1 Gene by Targeted Adaptive Nanopore Sequencing in a Family with Retinitis Pigmentosa","authors":"Michael P. Backlund,&nbsp;Pauliina Repo,&nbsp;Harri Kangas,&nbsp;Kati Donner,&nbsp;Eeva-Marja Sankila,&nbsp;Julia Krootila,&nbsp;Maarjaliis Paavo,&nbsp;Kirmo Wartiovaara,&nbsp;Tero T. Kivelä,&nbsp;Joni A. Turunen","doi":"10.1155/2024/6580561","DOIUrl":"10.1155/2024/6580561","url":null,"abstract":"<p>Retinitis pigmentosa (RP) is a group of inherited degenerative retinal disorders affecting more than 1.5 million people worldwide. For 30-50% of individuals with RP, the genetic cause remains unresolved by current clinical diagnostic gene panels. It is likely explained by variants in novel RP-associated genes or noncoding regulatory regions, or by complex genetic alterations such as large structural variants. Recent developments in long-read sequencing techniques have opened an opportunity for efficient analysis of complex genetic variants. We analysed a Finnish family with dominantly inherited RP affecting six individuals in three generations. Two affected individuals underwent a comprehensive clinical examination in combination with a clinical diagnostic gene panel, followed by whole exome sequencing in our laboratory. They exhibited typical signs of RP, yet initial sequence analysis found no causative variants. Reanalysis of the sequencing data detected a LINE-1 (L1) retrotransposon insertion of unknown size in exon 4 of the RP1 axonemal microtubule-associated (<i>RP1</i>) gene. The large chimeric L1 insertion that segregated with the disease was further characterised using targeted adaptive nanopore sequencing of <i>RP1</i>, allowing us to identify a 5.6 kb L1 transposable element insertion in <i>RP1</i> as the cause of RP in this family with dominantly inherited RP.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139790533","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}

{"title":"Functional Analysis of 3′UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia","authors":"Javier Sanguino Otero,&nbsp;Carmen Rodríguez-Jiménez,&nbsp;Jose Mostaza Prieto,&nbsp;Carlos Rodríguez-Antolín,&nbsp;Ana Carazo Alvarez,&nbsp;Francisco Arrieta Blanco,&nbsp;Sonia Rodríguez-Nóvoa","doi":"10.1155/2024/9964734","DOIUrl":"10.1155/2024/9964734","url":null,"abstract":"<p>Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence of 1 in 200-250 individuals. Patients with FH are at increased risk of premature coronary artery disease. Early diagnosis and treatment are essential for improving clinical outcomes. In many cases, however, the genetic diagnosis is not confirmed. At present, routine genetic testing does not analyze the 3^′UTR regions of <i>LDLR</i> and <i>PCSK9</i>. However, 3^′UTR-single nucleotide variants could be of interest because they can modify the target sequence of miRNAs that regulate the expression of these genes. Our study fully characterizes the 3^′UTR regions of <i>LDLR</i> and <i>PCSK9</i> in 409 patients with a suspected diagnosis of FH using next-generation sequencing. In 30 of the 409 patients, we found 21 variants with an allelic frequency of &lt;1%; 14 of them at 3^′UTR-<i>LDLR</i> and 8 at 3^′UTR-<i>PCSK9</i>. The variants’ pathogenicity was studied <i>in silico</i>; subsequently, a number of the variants were functionally validated using luciferase reporter assays. <i>LDLR</i>:c.^∗653G &gt; C showed a 41% decrease in luciferase expression, while <i>PCSK9</i>:c.^∗950C &gt; T showed a 41% increase in PCSK9 expression, results that could explain the hypercholesterolemia phenotype. In summary, the genetic analysis of the 3^′UTR regions of <i>LDLR</i> and <i>PCSK9</i> could improve the genetic diagnosis of FH.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139792868","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}

{"title":"A De Novo Noncoding RARB Variant Associated with Complex Microphthalmia Alters a Putative Regulatory Element","authors":"Maria R. Replogle,&nbsp;Samuel Thompson,&nbsp;Linda M. Reis,&nbsp;Elena V. Semina","doi":"10.1155/2024/6619280","DOIUrl":"10.1155/2024/6619280","url":null,"abstract":"<p>Retinoic acid receptor beta (<i>RARB</i>) is a transcriptional regulator crucial for coordinating retinoic acid- (RA-) mediated morphogenic movements, cell growth, and differentiation during eye development. Loss- or gain-of-function <i>RARB</i> coding variants have been associated with microphthalmia, coloboma, and anterior segment defects. We identified a <i>de novo</i> variant c.157+1895G&gt;A located within a conserved region (CR1) in the first intron of <i>RARB</i> in an individual with complex microphthalmia and significant global developmental delay. Based on the phenotypic overlap, we further investigated the possible effects of the variant on mRNA splicing and/or transcriptional regulation through <i>in silico</i> and functional studies. <i>In silico</i> analysis identified the possibility of alternative splicing, suggested by one out of three (HSF, SpliceAI, and MaxEntScan) splicing prediction programs, and a strong indication of regulatory function based on publicly available DNase hypersensitivity, histone modification, chromatin folding, and ChIP-seq data sets. Consistent with the predictions of SpliceAI and MaxEntScan, <i>in vitro</i> minigene assays showed no effect on <i>RARB</i> mRNA splicing. Evaluation of CR1 for a regulatory role using luciferase reporter assays in human lens epithelial cells demonstrated a significant increase in the activity of the <i>RARB</i> promoter in the presence of wild-type CR1. This activity was further significantly increased in the presence of CR1 carrying the c.157+1895G&gt;A variant, suggesting that the variant may promote <i>RARB</i> overexpression in human cells. Induction of <i>RARB</i> overexpression in human lens epithelial cells resulted in increased cell proliferation and elevated expression of <i>FOXC1</i>, a known downstream target of RA signaling and a transcription factor whose down- and upregulation is associated with ocular phenotypes overlapping the <i>RARB</i> spectrum. These results support a regulatory role for the CR1 element and suggest that the <i>de novo</i> c.157+1895G&gt;A variant affecting this region may alter the proper regulation of <i>RARB</i> and, as a result, its downstream genes, possibly leading to abnormal development.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139592340","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}

{"title":"Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)","authors":"Seda Susgun,&nbsp;Afif Ben-Mahmoud,&nbsp;Franz Rüschendorf,&nbsp;Bonsu Ku,&nbsp;Syeda Iqra Hussain,&nbsp;Solveig Schulz,&nbsp;Oliver Puk,&nbsp;Saskia Biskup,&nbsp;Jonathan D. J. Labonne,&nbsp;Dilan Wellalage Don,&nbsp;Vijay Gupta,&nbsp;Tae-Ik Choi,&nbsp;Saadullah Khan,&nbsp;Naveed Wasif,&nbsp;Yves Lacassie,&nbsp;Lawrence C. Layman,&nbsp;Sibel Aylin Ugur Iseri,&nbsp;Cheol-Hee Kim,&nbsp;Hyung-Goo Kim","doi":"10.1155/2024/5518289","DOIUrl":"10.1155/2024/5518289","url":null,"abstract":"<p>Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as <i>PIG</i> and <i>PGAP</i> genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. <i>PGAP2</i> stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in <i>PGAP2</i> in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with <i>PGAP2</i> variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with <i>PGAP2</i> variants.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381426","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}

{"title":"Disruption of OVOL2 Distal Regulatory Elements as a Possible Mechanism Implicated in Corneal Endothelial Dystrophy","authors":"Lubica Dudakova,&nbsp;Lenka Noskova,&nbsp;Stanislav Kmoch,&nbsp;Martin Filipec,&nbsp;Ales Filous,&nbsp;Alice E. Davidson,&nbsp;Vasileios Toulis,&nbsp;Jana Jedlickova,&nbsp;Pavlina Skalicka,&nbsp;Hana Hartmannova,&nbsp;Viktor Stranecky,&nbsp;Jana Drabova,&nbsp;Drahuse Novotna,&nbsp;Marketa Havlovicova,&nbsp;Zdenek Sedlacek,&nbsp;Petra Liskova","doi":"10.1155/2024/4450082","DOIUrl":"10.1155/2024/4450082","url":null,"abstract":"<p>The genetic architecture of corneal endothelial dystrophies remains unknown in a substantial number of affected individuals. The proband investigated in the current study was diagnosed in the neonatal period with bilateral corneal opacification due to primary endothelial cell dysfunction. Neither his parents nor his sister had signs of corneal disease. Conventional karyotyping revealed a <i>de novo</i> translocation involving chromosomes 3 and 20, t(3;20)(q25;p11-12). Following genome and targeted Sanger sequencing analysis, the breakpoints were mapped at the nucleotide level. Notably, the breakpoint on chromosome 20 was identified to lie within the same topologically associated domain (TAD) as corneal endothelial dystrophy-associated gene <i>OVOL2</i>, and it is predicted to disrupt distal enhancers. The breakpoint at chromosome 3 is located within intron 2 of <i>PFN2</i>, which is currently not associated with any human disease. Further interrogation of the proband’s genome failed to identify any additional potentially pathogenic variants in corneal endothelial dystrophy-associated genes. Disruption of a candidate <i>cis</i>-regulatory element and/or positional effects induced by translocation of <i>OVOL2</i> to a novel genomic context may lead to an aberrant <i>OVOL2</i> expression, a previously characterized disease mechanism of corneal endothelial dystrophy. Further research is necessary to explore how disruption of regulatory elements may elucidate genetically unsolved corneal endothelial dystrophies.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386823","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}

{"title":"Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG/AMP Framework","authors":"S. S. Cornelis, M. Bauwens, L. Haer-Wigman, M. De Bruyne, Madhulatha Pantrangi, E. De Baere, R. Hufnagel, C. Dhaenens, Frans P. M. Cremers","doi":"10.1155/2023/6815504","DOIUrl":"https://doi.org/10.1155/2023/6815504","url":null,"abstract":"Biallelic variants in ABCA4 cause Stargardt disease (STGD1), the most frequent heritable macular disease. Determination of the pathogenicity of variants in ABCA4 proves to be difficult due to (1) the high number of benign and pathogenic variants in the gene; (2) the presence of many rare ABCA4 variants; (3) the presence of complex alleles for which phasing data are absent; (4) the extensive variable expressivity of this disease and (5) reduced penetrance of hypomorphic variants. Therefore, the classification of many variants in ABCA4 is currently of uncertain significance. Here, we complemented the ABCA4 Leiden Open Variation Database (LOVD) with data from ~11,000 probands with ABCA4-associated inherited retinal diseases from literature up to the end of 2020. We carefully adapted the ACMG/AMP classifications to ABCA4 incorporating ClinGen recommendations and assigned these classifications to all 2,246 unique variants from the ABCA4 LOVD to increase the knowledge of pathogenicity. In total, 1,248 variants were categorized with a likely pathogenic or pathogenic classification, whereas 194 variants were categorized with a likely benign or benign classification. This uniform and improved structured reclassification, incorporating the largest dataset of ABCA4-associated retinopathy cases so far, will improve both the diagnosis as well as genetic counselling for individuals with ABCA4-associated retinopathy.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"60 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139155220","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}

{"title":"Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes","authors":"Michael R. Fiorini, Allison A. Dilliott, Sali M. K. Farhan","doi":"10.1155/2023/8620557","DOIUrl":"https://doi.org/10.1155/2023/8620557","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease affecting approximately two per 100,000 individuals globally. While there are many benefits to offering early genetic testing to people with ALS, this has also led to an increase in the yield of novel variants of uncertain significance in ALS-associated genes. Computational (in silico) predictors, including REVEL and CADD, are widely employed to provide supporting evidence of pathogenicity for variants in conjunction with clinical, molecular, and other genetic evidence. However, in silico predictors are developed to be broadly applied across the human genome; thus, their ability to evaluate the consequences of variation in ALS-associated genes remains unclear. To resolve this ambiguity, we surveyed 20 definitive and moderate ClinGen-defined ALS-associated genes from two large, open-access ALS sequencing datasets (total people with <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\"> <mtext>ALS</mtext> <mo>=</mo> <mn>8,230</mn> </math> ; <math xmlns=\"http://www.w3.org/1998/Math/MathML\" id=\"M2\"> <mtext>controls</mtext> <mo>=</mo> <mn>9,671</mn> </math> ) to investigate REVEL and CADD’s ability to predict which variants are most likely to be disease-causing in ALS. While our results indicate a predetermined pathogenicity threshold for REVEL that could be of clinical value for classifying variants in ALS-associated genes, an accurate threshold was not evident for CADD, and both in silico predictors were of limited value for resolving which variants of uncertain significance (VUS) may be likely pathogenic in ALS. Our findings allow us to provide important recommendations for the use of REVEL and CADD scores for variants and indicate that both tools should be used with caution when attempting to evaluate the pathogenicity of VUSs in ALS genetic testing.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"55 10","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136349044","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}