Human Mutation最新文献

{"title":"Genome Sequencing of Idiopathic Speech Delay","authors":"Else Eising,&nbsp;Arianna Vino,&nbsp;Heather L. Mabie,&nbsp;Thomas F. Campbell,&nbsp;Lawrence D. Shriberg,&nbsp;Simon E. Fisher","doi":"10.1155/2024/9692863","DOIUrl":"10.1155/2024/9692863","url":null,"abstract":"<p>Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of <i>FOXP2</i> provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of <i>de novo</i> variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in <i>SETD1A</i>, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic <i>SETD1A</i> variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of <i>SPTBN1</i> and <i>ARF3</i>. Overall, this study expands the phenotype spectrum associated with pathogenic <i>SETD1A</i> variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140369922","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":"Novel Synonymous and Deep Intronic Variants Causing Primary and Secondary Pyruvate Dehydrogenase Complex Deficiency","authors":"Helene Bruhn,&nbsp;Karin Naess,&nbsp;Sofia Ygberg,&nbsp;Lucía Peña-Pérez,&nbsp;Nicole Lesko,&nbsp;Rolf Wibom,&nbsp;Christoph Freyer,&nbsp;Henrik Stranneheim,&nbsp;Anna Wedell,&nbsp;Anna Wredenberg","doi":"10.1155/2024/1611838","DOIUrl":"10.1155/2024/1611838","url":null,"abstract":"<p>Pyruvate dehydrogenase complex deficiency (PDCD) is a defect of aerobic carbohydrate metabolism that causes neurological disorders with varying degrees of severity. We report the clinical, biochemical, and molecular findings in patients with primary and secondary PDCD caused by novel atypical genetic variants. Whole-genome sequencing (WGS) identified the synonymous variants c.447A&gt;G, p.(Lys149=) and c.570C&gt;T, p.(Cys190=) in pyruvate dehydrogenase E1 subunit alpha 1 (<i>PDHA1</i>), the deep intronic variants c.1023+2267G&gt;A and c.1023+2302A&gt;G in pyruvate dehydrogenase complex component X (<i>PDHX</i>), and c.185+15054G&gt;A in thiamine pyrophosphokinase (<i>TPK1</i>). Analysis by Sanger and RNA sequencing of cDNA from patient blood and/or cultured fibroblasts showed that the synonymous variants in <i>PDHA1</i> lead to aberrant splicing and skipping of exons 5 and 5-6 in one of the patients and transcripts lacking exon 6 in the other. The deep intronic variants in <i>PDHX</i> and <i>TPK1</i> lead to insertion of intronic sequence in the corresponding transcripts. The splice defects in <i>PDHA1</i> were more pronounced in cultured fibroblasts than in blood. Our findings expand the spectrum of pathogenic variants causing PDCD and highlight the importance of atypical variants leading to aberrant splicing. The severity of the splice defects and resulting biochemical dysfunction varied between tissues, stressing the importance of performing biochemical and transcript analysis in affected tissues. The two males with hemizygous synonymous <i>PDHA1</i> variants have a mild phenotype and higher PDH enzyme activity than expected, which is consistent with aberrant but leaky splicing with a proportion of the transcripts remaining correctly spliced.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140381810","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":"Estimation of the Age of the Kashubian-Specific Pathogenic NPHS2 Variant Responsible for Hereditary Steroid-Resistant Nephrotic Syndrome Points to Its Recent Local Origin","authors":"M. Jankowski,&nbsp;P. Daca-Roszak,&nbsp;I. Bałasz-Chmielewska,&nbsp;A. Ustaszewski,&nbsp;A. Żurowska,&nbsp;B. S. Lipska-Ziętkiewicz,&nbsp;E. Ziętkiewicz","doi":"10.1155/2024/8205102","DOIUrl":"10.1155/2024/8205102","url":null,"abstract":"<p>Steroid-resistant nephrotic syndrome (SRNS) is a highly heterogenic kidney disorder resulting from genetic abnormalities or immune system dysfunction affecting the establishment and maintenance of the glomerular filtration barrier. The most common cause of genetic SRNS is biallelic pathogenic variants in <i>NPHS2</i> gene, especially in individuals with an infantile or childhood onset. The type of the <i>NPHS2</i> defect implies the course of the disease and the stage of its onset and differs across populations. In a cohort of Polish patients with SRNS, a unique profile of the disease-related <i>NPHS2</i> variants was identified in patients from northern Poland inhabited by Kashubs, a minority West-Slavic ethnic group known for a local increase of the frequency of several pathogenic variants. Among Kashubian families, the compound heterozygotes c.686G&gt;A/c.1032delT and a single c.1032delT homozygote were the only underlying cause of SRNS. The restricted, Kashubian-only pattern of c.1032delT occurrence, suggesting the founder effect, prompted us to conduct a detailed analysis of its haplotype background to estimate the age of the c.1032delT origin. Eight Kashubian SRNS families were genotyped using the Infinium Global Screening Array-24. The haplotype background analysis was performed using an in-house pipeline designed to solve the phase of the heterozygous genotype data. The age of the c.1032delT mutation was calculated using the gamma method based on the genetic length of ancestral haplotypes shared between two or more individuals carrying this variant. The results of our study indicated a very recent origin of the c.1032delT mutation (~240 years). Genetic screening performed in the general Polish population control corroborates the assumption that the mutation occurred on the specific Kashubian haplotype background. The identification of ancestry-specific Kashubian pathogenic variant can help to develop effective screening and diagnostic strategies as a part of personalized medicine approach in the region.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140223977","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":"Whole-Exome Sequencing Analysis Identifies Risk Genes in Atlantoaxial Dislocation Patients with Sandwich Fusion","authors":"Guodong Gao,&nbsp;Yinglun Tian,&nbsp;Kan-Lin Hung,&nbsp;Dongwei Fan,&nbsp;Nanfang Xu,&nbsp;Shenglin Wang","doi":"10.1155/2024/5021689","DOIUrl":"10.1155/2024/5021689","url":null,"abstract":"<p>Sandwich fusion of Klippel-Feil syndrome (KFS), which is a rare congenital disorder involving the fusion of cervical vertebrae, poses significant challenges in the diagnosis and treatment of atlantoaxial dislocation (AAD). While the disorder’s genetic basis is not well-understood, the rarity of the sandwich fusion makes it difficult to study. Whole-exome sequencing (WES) was conducted on 68 unrelated Chinese patients with sandwich fusion. The study compared their genetic data with a control group of 219 individuals without musculoskeletal disorders. Various analyses, including mutational burden assessments, were employed to identify potential pathogenic genes. The study identified significant genetic variations in patients with sandwich fusion, highlighting genes like <i>KMT5A</i>, <i>HYDIN</i>, and <i>PCDHB4</i> as potential contributors. Notably, severe cases exhibited oligogenic effects, with mutations in genes like <i>MEOX1</i> associated with the severity of spinal issues. These findings offer critical insights into the genetic basis of sandwich fusion and provide a foundation for future research and therapeutic development.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140249713","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":"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}