Journal of Medical Genetics最新文献

{"title":"Ending nuclear weapons, before they end us.","authors":"Chris Zielinski","doi":"10.1136/jmg-2025-110897","DOIUrl":"10.1136/jmg-2025-110897","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"495-496"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078500","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":"<i>RNU4-2</i> monoallelic variants as a leading cause of syndromic neurodevelopmental disorder, including in patients with parental consanguinity.","authors":"Aida M Bertoli-Avella, Christian A Ganoza, Mariana Ferreira, Maryam Najafi, Daniel L Polla, Krishna Kandaswamy, Kornelia Tripolszki, Peter Bauer, Jorge Pinto Basto","doi":"10.1136/jmg-2024-110556","DOIUrl":"10.1136/jmg-2024-110556","url":null,"abstract":"<p><p>We analysed rare variants in the non-coding <i>RNU4-2</i> gene as a potential cause of neurodevelopmental disorder (NDD) and intellectual disability (ID) in a large cohort of individuals enriched for parental consanguinity.Genome sequencing (GS) data from 22 928 individuals in our Biodatabank were queried for rare, monoallelic variants in <i>RNU4-2</i> From these, 4918 patients presented with NDD/ID. Human Phenotype Ontology (HPO)-encoded clinical information was extracted and analysed using the ontologyX R package.Nearly 50% of the 4918 patients with NDD/ID reported parental consanguinity. Eight relevant heterozygous <i>RNU4-2</i> variants were identified in 28 patients. n.64_65insT was the most frequently detected variant (20 patients, 71%), while the remaining variants were found in 1 or 2 patients each (n.65A>G, n.66A>G, n.67A>G, n.70T>C, n.76C>T, n.95C>G and n.135A>C). Four variants are novel or ultra-rare, and two of them are in the 3' stem loops. HPO-based analysis revealed a consistent syndromic phenotype characterised by NDD, abnormal brain morphology, hypotonia, global developmental delay, microcephaly, seizures, atypical behaviour and facial dysmorphism. <i>RNU4-2</i> variants accounted for approximately 0.55% of NDD/ID cases in our full cohort, and 0.25% in the subset of consanguineous patients (all genetic causes included).This study underscores the significance of <i>RNU4-2</i> as a major genetic cause of NDD/ID, extending its relevance to consanguineous patients, where recessive disorders are often suspected. We advocate for the re-evaluation of existing GS data to uncover potential diagnoses and emphasise the importance of GS as a first-tier diagnostic test.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"536-539"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142685","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":"Economic evaluation of personalised versus conventional risk assessment for women who have undergone testing for hereditary breast and ovarian cancer genes: a modelling study.","authors":"Qin Xi, Nichola Fennell, Stephanie Archer, Marc Tischkowitz, Antonis C Antoniou, Stephen Morris","doi":"10.1136/jmg-2024-109948","DOIUrl":"10.1136/jmg-2024-109948","url":null,"abstract":"<p><strong>Background: </strong>The management of women with germline pathogenic variants (GPVs) in breast (BC) and ovarian cancer (OC) susceptibility genes is focused on surveillance and risk-reducing surgery/medication. Most women are assigned an average range of risk and treated accordingly, but it is possible to personalise this. Here, we explore the economic impact of risk personalisation.</p><p><strong>Method: </strong>We compared two strategies for risk stratification for female participants: conventional risk assessment (CRA), which only involves information from genetic testing and personalised risk assessment (PRA), using genetic and non-genetic risk modifiers. Three different versions of PRA were compared, which were combinations of polygenic risk score and questionnaire-based factors. A patient-level Markov model was designed to estimate the overall National Health Service cost and quality-adjusted life years (QALYs) after risk assessment. Results were given for 20 different groups of women based on their GPV status and family history.</p><p><strong>Results: </strong>Across the 20 scenarios, the results showed that PRA was cost-effective compared with CRA using a £20 000 per QALY threshold in women with a GPV in <i>PALB2</i> who have OC or BC+OC family history, and women with a GPV in <i>ATM</i>, <i>CHEK2</i>, <i>RAD51C</i> or <i>RAD51D</i>. For women with a GPV in <i>BRCA1</i> or <i>BRCA2</i>, women with no pathogenic variant and women with a GPV in <i>PALB2</i> who have unknown family history or BC family history, CRA was more cost-effective. PRA was cost-effective compared with CRA in specific situations predominantly associated with moderate-risk BC GPVs (<i>RAD51C</i>/<i>RAD51D</i>/<i>CHEK2</i>/<i>ATM</i>), while CRA was cost-effective compared with PRA predominantly with high-risk BC GPVs (<i>BRCA1</i>/<i>BRCA2</i>/<i>PALB2</i>).</p><p><strong>Conclusion: </strong>PRA was cost-effective in specific situations compared with CRA in the UK for assessment of women with or without GPVs in BC and OC susceptibility genes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"450-456"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006961","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":"Effects of higher-than-expected control population allele frequency on classification of loss-of-function variants in cancer susceptibility genes.","authors":"Miriam J Smith, George J Burghel, D Gareth Evans","doi":"10.1136/jmg-2025-110703","DOIUrl":"10.1136/jmg-2025-110703","url":null,"abstract":"<p><p>A query was sent to the cancer predisposition gene variant database Cancer Variant Interpretation Group UK, on the nonsense variant in NM_032043.3(<i>BRIP1</i>):c.2392C>T,p.(Arg798Ter). The submitter classified this as a variant of uncertain significance, providing very strong variant effect evidence with the intention of adding supporting pedigree information, according to the guidelines used for classification. However, the relatively high population frequency in the UKB cohort of 367/439 920 (0.083%) was a concern as it is higher than expected for the disease frequency, which would reduce the predicted pathogenicity score. This situation highlights the increasing concerns over the use of population data in pathogenicity classification of truncating/loss-of-function (LoF) variants in known cancer predisposition genes, particularly since the addition of UKB control data. Here, we have conducted a series of case-control comparisons for common truncating variants in known breast/ovarian cancer-associated genes, as well as <i>LZTR1</i>-related schwannomatosis, to address this issue using our Manchester cancer screening population compared with controls in UKB data.Our data show strong ORs for these common truncating variants. We propose that for truncating variants in cancer susceptibility genes with a significant case-control OR, apparently conflicting population frequency evidence criteria should be avoided.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"464-466"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029917","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":"<i>LSM1</i> c.231+4A>C hotspot variant is associated with a novel neurodevelopmental syndrome: first patient cohort.","authors":"Sivan Reytan Miron, Alina Kurolap, Bassam Abu-Libdeh, Abdel Salam Abu-Libdeh, Clara Velmans, Florian Erger, Vera Riehmer, Tzung-Chien Hsieh, Hellen Lesmann, Adi Reches, Chofit Chai Gadot, Adi Mory, Motee Al-Ashhab, Christian Netzer, Nadirah Damseh, Hagit Baris Feldman","doi":"10.1136/jmg-2024-110574","DOIUrl":"10.1136/jmg-2024-110574","url":null,"abstract":"<p><strong>Background: </strong>The <i>LSM1</i> gene encodes a subunit of the conserved LSM1-7 protein complex involved in messenger RNA (mRNA) metabolism. Variants in the <i>LSM1</i> gene have been described in two separate case reports. The first published report identified the homozygous splice-site variant c.231+4A>C, while the second reported a homozygous missense variant. Nevertheless, variation in <i>LSM1</i> has yet to be established as disease-causing in humans.</p><p><strong>Methods: </strong>Through exome sequencing and detailed phenotyping, we report six syndromic paediatric patients with the homozygous c.231+4A>C variant in the <i>LSM1</i> gene, collected via GeneMatcher. GestaltMatcher was used to analyse facial feature similarity, and real-time quantitative PCR (RT-qPCR) confirmed the splice defect caused by the variant. Haplotype analysis assessed whether this variant resulted from independent occurrences or a common ancestral haplotype.</p><p><strong>Results: </strong>Patients presented with dysmorphic facial features, developmental delay and multisystemic involvement, including urological, cardiac and skeletal manifestations, showcasing the phenotypic spectrum of this syndrome. RT-qPCR confirmed that the c.231+4A>C variant causes exon 3 skipping, producing negligible <i>wild-type LSM1</i> mRNA expression. Elevated mutant isoform expression confirmed pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We identified this variant in the Muslim Arab and Ashkenazi Jewish populations and determined that it represents a hotspot variant through haplotype analysis.</p><p><strong>Conclusion: </strong>Our findings establish <i>LSM1</i>, and specifically the c.231+4A>C homozygous variant, as causative for a novel autosomal recessive syndromic neurodevelopmental disorder. These results expand the understanding of <i>LSM1</i>-related diseases and provide a foundation for further investigation of its molecular mechanisms.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"441-449"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015469","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":"Optimising the molecular investigation of the FSHD locus: an integrated workflow using single molecule optical mapping and Southern blot analysis.","authors":"Joowon Jang, Hobin Sung, Jung-Ae Lee, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong","doi":"10.1136/jmg-2024-110382","DOIUrl":"10.1136/jmg-2024-110382","url":null,"abstract":"<p><strong>Purpose: </strong>Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder caused by contraction or hypomethylation of the D4Z4 repeat array located at chromosome 4q35. For the disease to manifest, a permissive haplotype is required, as it enables the pathogenic expression of the <i>DUX4</i> gene. FSHD cases often involve complex rearrangements, such as intrachromosomal rearrangements and translocations, which complicate diagnosis using conventional methods. This study focuses on evaluating the diagnostic potential of single molecule optical mapping (SMOM) for FSHD with complex rearrangements, particularly in cases involving 4q-10q translocations, which present challenges for detection by SMOM alone. Furthermore, we propose an integrated diagnostic strategy, combining SMOM with complementary methods, to improve accuracy in these challenging cases.</p><p><strong>Methods: </strong>We reviewed the test results of 238 patients with suspected FSHD, and 25 participants with presumed complex rearrangements were included in this study. SMOM was performed on these participants, and the results were manually reviewed and compared with those obtained from Southern blot (SB) analysis.</p><p><strong>Results: </strong>Nine patients carrying 4q-10q translocation exhibited discrepancies between the two methods. Linear regression analysis revealed a significant discrepancy in chromosomal assignment between SB and SMOM in cases suspected of translocation.</p><p><strong>Conclusions: </strong>Given the complex nature of FSHD, none of the current methods can independently provide a definitive diagnosis. As misdiagnosis may occur when relying on a single technique, we propose an integrated diagnostic approach, with SMOM as the first-line test.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"467-475"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024661","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":"Identification of <i>MACF1</i> as a causative gene of generalised epilepsy.","authors":"Xiao-Yun Lei, Meng-Wen Zhang, Hui Sun, Wang Song, Xiao-Yu Liang, Cui-Shan Wang, Sheng Luo, Bing-Mei Li, Xiao-Rong Liu, Yao Wang, Yang Tian, Qian Peng, Jie Wang, Heng Meng, Na He, Wei-Ping Liao","doi":"10.1136/jmg-2025-110699","DOIUrl":"10.1136/jmg-2025-110699","url":null,"abstract":"<p><strong>Background: </strong>The microtubule actin crosslinking factor 1 (<i>MACF1)</i> gene encodes microtubule-microfilament cross-linking factor 1 that plays an essential role in the embryonic brain development. <i>MACF1</i> variants were associated with lissencephaly-9 (LIS9). However, the <i>MACF1</i>-epilepsy relationship was unknown.</p><p><strong>Methods: </strong>Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of <i>MACF1</i> in epilepsy and neurodevelopment.</p><p><strong>Results: </strong>Two de novo heterozygous and eight biallelic <i>MACF1</i> variants were identified in 10 unrelated patients. The variants presented significantly high excess by multiple statistical analyses. All patients were diagnosed with generalised epilepsy, among whom three patients presented with neurodevelopmental delay. <i>MACF1</i> was expressed throughout the lifespan, with three major peaks in the fetal, early childhood and adulthood stages, consistent with seizure onset ages of the patients. The highest expression in adulthood was in the thalamus nucleus, potentially associated with the pathogenesis of generalised epilepsy. The single-cell sequencing in organoids showed <i>MACF1</i> is widely expressed in the developing brain, especially in the early stage, suggesting a vital role in neurodevelopment. Genotype-phenotype association analysis revealed that LIS9-associated variants were featured by de novo monoallelic variants clustered within the C-terminal; the autism spectrum disorder-associated variants were mainly de novo monoallelic variants located at the spectrin-repeat rod domains. In contrast, the epilepsy-associated variants were biallelic missense variants, and those in the plakin domain were potentially associated with neurodevelopment delay.</p><p><strong>Significance: </strong><i>MACF1</i> is potentially a novel causative gene of generalised epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"484-493"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021446","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":"Rare missense variants in <i>FNDC1</i> are associated with severe adolescent idiopathic scoliosis.","authors":"Wu-Lin Charng, Gabe Haller, Julia Whittle, Momchil Nikolov, Addison Avery, Jose Morcuende, Philip Giampietro, Cathy Raggio, Nancy Miller, Anne E Justice, Natasha T Strande, Mark Seeley, Dale L Bodian, Carol A Wise, Diane S Sepich, Matthew B Dobbs, Christina A Gurnett","doi":"10.1136/jmg-2024-110586","DOIUrl":"10.1136/jmg-2024-110586","url":null,"abstract":"<p><strong>Background: </strong>Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.</p><p><strong>Methods: </strong>To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. <i>FNDC1</i> function was investigated in <i>fndc1</i> null mutant zebrafish.</p><p><strong>Results: </strong>Rare variants were enriched in 84 genes, including <i>RAF1</i> (Noonan syndrome), <i>FBN1</i> (Marfan syndrome) and <i>FNDC1,</i> in individuals with severe AIS. <i>FNDC1</i>, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). <i>FNDC1</i> variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, <i>FNDC1</i> rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the <i>fndc1</i> locus in zebrafish resulted in increased bone mineral density.</p><p><strong>Conclusion: </strong>We broadened the phenotype associated with <i>RAF1</i> and <i>FBN1</i> variants and identified <i>FNDC1</i> as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of <i>FNDC1</i> missense variants with AIS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"427-435"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015097","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":"Electronic health record-based registry for identification of individuals at risk for hereditary cancer syndromes.","authors":"Vinit Singh, Thomas E Rafter, Mohamad Sharbatji, Jing Liu, Quiana Brown, Karina Brierley, Claire Healy, Rosa M Xicola, Nitu M Kashyap, Xavier Llor","doi":"10.1136/jmg-2025-110718","DOIUrl":"10.1136/jmg-2025-110718","url":null,"abstract":"<p><strong>Background: </strong>Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis.</p><p><strong>Methods: </strong>National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of 'at-risk'. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients.</p><p><strong>Results: </strong>Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001).</p><p><strong>Conclusions: </strong>This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"457-463"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996437","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":"Short stature, brachydactyly and joint contractures associated with novel <i>FBN2</i> variants in two families.","authors":"Petra Loid, Fan Wang, Otto Lennartsson, Mari Muurinen, Alice Costantini, Sakshi Vats, Maria Lodefalk, Ola Nilsson, Outi Mäkitie","doi":"10.1136/jmg-2024-110533","DOIUrl":"10.1136/jmg-2024-110533","url":null,"abstract":"<p><strong>Background: </strong>Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by <i>FBN2</i>, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.</p><p><strong>Methods and results: </strong>We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the <i>FBN2</i> gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The <i>FBN2</i> deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.</p><p><strong>Conclusion: </strong>Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of <i>FBN2-</i>related phenotypes. The study supports the role of <i>FBN2</i> variants in growth failure and expands the molecular spectrum of <i>FBN2</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"436-440"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811499","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}