Clinical Genetics最新文献_第5页

Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients. 1例重度DEE-SWAS女性患者CNKSR2致病变异鉴定及强XCI检测及男性患者表型扩增

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-27 DOI: 10.1111/cge.70054

Yu Katata, Yukimune Okubo, Haruhiko Nakamura, Naoya Saijo, Masakiyo Hayasaka, Jun Takayama, Shigeo Kure, Atsuo Kikuchi

{"title":"Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients.","authors":"Yu Katata, Yukimune Okubo, Haruhiko Nakamura, Naoya Saijo, Masakiyo Hayasaka, Jun Takayama, Shigeo Kure, Atsuo Kikuchi","doi":"10.1111/cge.70054","DOIUrl":"https://doi.org/10.1111/cge.70054","url":null,"abstract":"Connector enhancer of kinase suppressor of Ras2 (CNKSR2) is critical in neuronal dendrite growth. Hemizygous pathogenic variants of CNKSR2, which is located at Xp22.12, are associated with intellectual disability, epilepsy, and developmental and epileptic encephalopathy with spike wave activation during sleep. As an X-linked recessive genetic disorder, neurological symptoms usually manifest in males, while female carriers are typically asymptomatic. Here, we report a girl (Patient 1) and boy (Patient 2) with a pathogenic truncated variant of CNKSR2. Patient 1 had intractable epilepsy and severe developmental regression; her electroencephalogram showed continuous spike-and-wave activity during sleep. Whole-genome sequencing (WGS) revealed a heterozygous CNKSR2 c.2134C>T, p.(Arg712Ter) variant (de novo, previously reported), and X-chromosome inactivation analysis of her white blood cell DNA showed marked skewing (85:15). Her clinical symptoms were more severe than those of previously reported female patients, but they improved with ethosuximide and sulthiame treatment. Patient 2 had epilepsy and Angelman syndrome-like symptoms. WGS revealed a Clinical Genetics hemizygous c.492C>A, p (Cys164Ter) CNKSR2 variant (maternal or novel). The strength of the X-chromosome inactivation skewing may be related to severity. These novel pathogenic CNKSR2 variants have expanded the phenotypic spectrum of this disease.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Molecular Genetics in 1991 Arrhythmia Probands and 2782 Relatives in Norway: Results From 17 Years of Genetic Testing in a National Laboratory” 对“1991年心律失常先证者和挪威2782名亲属的分子遗传学：来自一个国家实验室17年基因检测的结果”的更正

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-26 DOI: 10.1111/cge.70040

引用次数: 0

RNA Analysis Uncovers Pathogenic PARN Variant in Dyskeratosis Congenita. RNA分析揭示先天性角化不良的致病性PARN变异。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-26 DOI: 10.1111/cge.70037

Daria Akimova, Natalia Semenova, Tatiana Cherevatova, Mikhail Skoblov

{"title":"RNA Analysis Uncovers Pathogenic PARN Variant in Dyskeratosis Congenita.","authors":"Daria Akimova, Natalia Semenova, Tatiana Cherevatova, Mikhail Skoblov","doi":"10.1111/cge.70037","DOIUrl":"https://doi.org/10.1111/cge.70037","url":null,"abstract":"Dyskeratosis congenita (DC) is a rare genetic disorder caused by impaired telomere maintenance, leading to diverse clinical manifestations, including bone marrow failure, mucocutaneous abnormalities, and multi-organ dysfunction. Here, we report a 14-year-old male patient presenting with microcephaly, developmental delay, synostoses, cerebellar hypoplasia with ataxia, and an immunodeficiency condition, but lacking classical DC features such as nail dystrophy and skin hyperpigmentation. WGS revealed two variants in the PARN gene: a known pathogenic missense variant (c.1045C > T, p.Arg349Trp) and a novel intronic variant (c.178-28T > C). Functional RNA analysis demonstrated that the intronic variant disrupts the branch point sequence, leading to exon 4 skipping and nonsense-mediated decay (NMD) of a significant proportion of transcripts. This study confirms the pathogenicity of the intronic variant and underscores the importance of functional validation in interpreting noncoding variants, particularly in genetically heterogeneous disorders like DC. Our findings expand the molecular and phenotypic spectrum of PARN-related DC and highlight the utility of WGS reanalysis and RNA studies in resolving diagnostically challenging cases.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FSCN1 as a Candidate Gene for Syndromic Intellectual Disability? Evidence From a Recurrent Variant in an Iranian Cohort. FSCN1是综合征性智力残疾的候选基因？来自伊朗人群中一种复发性变异的证据。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-25 DOI: 10.1111/cge.70051

Hossein Najmabadi, Tara Akhtarkhavari, Ebrahim Shokouhian, Sanaz Arzhangi, Kimia Kahrizi

{"title":"FSCN1 as a Candidate Gene for Syndromic Intellectual Disability? Evidence From a Recurrent Variant in an Iranian Cohort.","authors":"Hossein Najmabadi, Tara Akhtarkhavari, Ebrahim Shokouhian, Sanaz Arzhangi, Kimia Kahrizi","doi":"10.1111/cge.70051","DOIUrl":"https://doi.org/10.1111/cge.70051","url":null,"abstract":"Intellectual disability (ID) is a genetically heterogeneous disorder, and many causative genes remain unidentified. FSCN1 encodes an actin-bundling protein essential for neuronal development, but its role in human neurodevelopmental disorders has not been clinically established. By revisiting data from a previously studied Iranian ID cohort, we identified two unrelated families carrying the same rare pathogenic missense variant in FSCN1 (c.665C>A; p.Ala222Asp). Affected individuals exhibited moderate to severe ID with consistent craniofacial features, including a prominent maxilla, long face, broad forehead, and thick lower lip. In silico tools predicted the variant as damaging and destabilizing, and the affected residue is highly conserved. This study provides the first clinical evidence linking FSCN1 to syndromic ID with craniofacial anomalies. The craniofacial features observed in our patients are consistent with experimental evidence from animal models. Together with supportive data from animal models, our findings suggest FSCN1 as a candidate gene for rare or ultra-rare forms of ID and warrant further functional studies to elucidate its precise pathogenic mechanisms.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular Landscape in Limb Anomalies: Diagnostic Yield and New Candidate Genes. 肢体异常的分子景观：诊断率和新的候选基因。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-21 DOI: 10.1111/cge.70048

Akram Mokhtari, Jade Charbonneau, Valancy Miranda, Khadijé Jizi, Marie-Ange Delrue, Patricia Egerszegi, Isabelle Thiffault, Philippe M Campeau

{"title":"Molecular Landscape in Limb Anomalies: Diagnostic Yield and New Candidate Genes.","authors":"Akram Mokhtari, Jade Charbonneau, Valancy Miranda, Khadijé Jizi, Marie-Ange Delrue, Patricia Egerszegi, Isabelle Thiffault, Philippe M Campeau","doi":"10.1111/cge.70048","DOIUrl":"https://doi.org/10.1111/cge.70048","url":null,"abstract":"Congenital limb anomalies remain without an etiological diagnosis in up to 65% of patients. To help close this gap, we describe the genetic diagnostic outcomes of a large cohort. Patients whose primary indication for genetic consultation was a limb anomaly were included from 2014 to 2024. Demographic, investigation, and diagnostic information were extracted, described, and compared. One hundred and thirty-two patients were included in the final cohort, with an average molecular diagnostic yield of 36%. The most common conditions were polydactyly (24%) and radial anomalies (19%). Fifty percent had syndromic features. Seven (5%) patients underwent chromosomal microarray (CMA) only, 81 (63%) CMA and a gene panel, and 43 (32%) subsequently underwent exome sequencing. Exome yielded a diagnosis in 11 (25%). We identified 25 novel mutations in known disease-causing genes, including TBX3 (3 cases) and expanded the phenotype of several loci, including BMP4 and HNRNPH2. Finally, we identified two new limb anomalies candidate loci, for which previously published mouse studies from other groups suggested roles in limb development: HOXA11 and a 2q31.1 deletion involving HOXD10 and HOXD12. This represents the second largest described limb anomalies cohort. Exome-wide sequencing associated with literature and database searches for mouse data represents an opportunity to identify novel etiologies in this group of disorders, including two candidate loci we identified.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies. TMEM17第二跨膜结构域的错义变异破坏了其稳定性和功能，并导致了广泛的纤毛病表型谱。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-21 DOI: 10.1111/cge.70042

Lucile Boutaud, Chunmei Li, Candice Moncler, Laure Verlin, Meriem Garfa-Traoré, Nicolas Bourgon, Dhruvin Akbari, Jeanne Porée, Valentina Serpieri, Marine Panza, Lynda Haddad, Patrick Nitschké, Jacqueline Aziza, Cristina Matt, Enza Maria Valente, Patricia Gargallo, Charlotte Dubucs, Tania Attié-Bitach, Michel R Leroux, Sophie Thomas

{"title":"Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies.","authors":"Lucile Boutaud, Chunmei Li, Candice Moncler, Laure Verlin, Meriem Garfa-Traoré, Nicolas Bourgon, Dhruvin Akbari, Jeanne Porée, Valentina Serpieri, Marine Panza, Lynda Haddad, Patrick Nitschké, Jacqueline Aziza, Cristina Matt, Enza Maria Valente, Patricia Gargallo, Charlotte Dubucs, Tania Attié-Bitach, Michel R Leroux, Sophie Thomas","doi":"10.1111/cge.70042","DOIUrl":"https://doi.org/10.1111/cge.70042","url":null,"abstract":"Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17-associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal-lethal condition (MKS).","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRCA2 c.156_157insAlu Founder Variant in Northern Portugal: An Insight Into Hereditary Breast and Ovarian Cancer Genetic Risk and Management. 葡萄牙北部BRCA2 c.156_157insAlu创始人变异：对遗传性乳腺癌和卵巢癌遗传风险和管理的洞察。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-15 DOI: 10.1111/cge.70046

Sílvia A C Duarte, Regina Arantes, Márcia Martins, Osvaldo Moutinho, Felisbina L Queiroga, Rosário Pinto-Leite

{"title":"BRCA2 c.156_157insAlu Founder Variant in Northern Portugal: An Insight Into Hereditary Breast and Ovarian Cancer Genetic Risk and Management.","authors":"Sílvia A C Duarte, Regina Arantes, Márcia Martins, Osvaldo Moutinho, Felisbina L Queiroga, Rosário Pinto-Leite","doi":"10.1111/cge.70046","DOIUrl":"https://doi.org/10.1111/cge.70046","url":null,"abstract":"The BRCA2 c.156_157insAlu variant is a Portuguese founder mutation implicated in hereditary breast and ovarian cancer (HBOC). This study aims to determine its occurrence and clinical implications in the northern interior region of Portugal. A retrospective study of 571 individuals referred for HBOC genetic counseling and testing between 2021 and 2024 was conducted. Genetic screening was performed using next-generation sequencing of 27 hereditary cancer genes, with confirmatory PCR for BRCA2 c.156_157insAlu. Pathogenic or likely pathogenic variants were detected in 19.8% of participants, with BRCA1/2 variants accounting for 5.4%. The BRCA2 c.156_157insAlu variant was identified in 6 individuals (25% of all BRCA2 pathogenic variants identified), including breast cancer patients and asymptomatic carriers. Clinically, it was associated with early onset and contralateral breast cancer. Cascade testing and genetic counseling were offered to at-risk relatives. The BRCA2 c.156_157insAlu variant remains a significant contributor to HBOC in northern Portugal. Its high local proportion among BRCA2 variants supports the implementation of targeted genetic testing strategies, enhancing early detection and personalized cancer risk management.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Role of Whole-Exome Sequencing and Methylation Analysis in Untangling Complex Facioscapulo-Humeral Muscular Dystrophy Cases. 全外显子组测序和甲基化分析在解开复杂的面肩胛骨-肱骨肌营养不良病例中的作用。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-11 DOI: 10.1111/cge.70044

Francesca Torri, Claudia Strafella, Liliana Vercelli, Giulio Gadaleta, Barbara Risi, Domenica Megalizzi, Luca Colantoni, Beatrice Ciurli, Mariaconcetta Rende, Massimiliano Filosto, Tiziana Mongini, Gabriele Siciliano, Emiliano Giardina, Giulia Ricci

{"title":"The Role of Whole-Exome Sequencing and Methylation Analysis in Untangling Complex Facioscapulo-Humeral Muscular Dystrophy Cases.","authors":"Francesca Torri, Claudia Strafella, Liliana Vercelli, Giulio Gadaleta, Barbara Risi, Domenica Megalizzi, Luca Colantoni, Beatrice Ciurli, Mariaconcetta Rende, Massimiliano Filosto, Tiziana Mongini, Gabriele Siciliano, Emiliano Giardina, Giulia Ricci","doi":"10.1111/cge.70044","DOIUrl":"https://doi.org/10.1111/cge.70044","url":null,"abstract":"Facioscapulo-humeral muscular dystrophy is characterized by a distinctive phenotype, although a wide range of clinical expressions is observed, possibly reflecting different disease progression rates or complex genetic mechanisms. To date, the diagnostic criteria for FSHD rely on identifying the genetic signature of the disease (reduced D4Z4 allele, permissive 4q allele, hypomethylation, and in some cases variants in modifier genes). However, interpreting genetic data requires careful correlation with the phenotype, especially in atypical cases. The study included a cohort of 42 patients with a D4Z4 contraction or belonging to a pedigree in which DRAs segregated but who were selected due to presenting atypical clinical features or an unexpected disease severity according to the Comprehensive Clinical Evaluation Form (CCEF). The 42 underwent 4q subtype analysis, DNA methylation assessment, whole-exome sequencing (WES) and segregation analysis. In 24 cases, WES identified likely pathogenic or pathogenic variants in genes associated with different neuromuscular disorders, in some cases possibly compatible with the observed phenotype. Methylation analysis proved useful in distinguishing asymptomatic and atypical cases, prompting differential diagnosis. Our results emphasize the importance of a detailed phenotypic characterization of patients with a suspicion of FSHD and, in the case of atypical phenotypes, the combination of D4Z4 sizing with other procedures such as WES.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy. RePOWER：原发性线粒体肌病患者的一项国际、前瞻性、非介入性登记。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-11 DOI: 10.1111/cge.70026

Amel Karaa, Amy Goldstein, Bruce H Cohen, Richard H Haas, Jerry Vockley, Gráinne S Gorman, Michelangelo Mancuso

{"title":"RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy.","authors":"Amel Karaa, Amy Goldstein, Bruce H Cohen, Richard H Haas, Jerry Vockley, Gráinne S Gorman, Michelangelo Mancuso","doi":"10.1111/cge.70026","DOIUrl":"https://doi.org/10.1111/cge.70026","url":null,"abstract":"Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is limited. The international RePOWER registry (NCT03048617) assessed genotypic and phenotypic relationships in PMM and identified patients for MMPOWER-3 (elamipretide Phase 3 study). RePOWER enrolled screened and ambulatory patients aged 16-80 years. With signs and/or symptoms of PMM (N = 376; 60.4% female; mean [SD] age 42.6 [14.4] years; ~75% with an mtDNA variant and ~25% with an nDNA variant). Baseline information, current symptoms, qualityoflife, and functional assessments (6-Minute Walk Test [6MWT], Triple-Timed Up-and-Go [3TUG] Test, and 5-Times Sit-to-Stand Test [5XSST]) were captured. Accredited laboratory and genetic testing methods were available to most patients. The majority of enrolled PMM patients presented with progressive external ophthalmoplegia and fatigue. US patients were observed to use more medical interventions. Compared to non-US patients, US patients did not perform as well on the 6MWT (mean 364.6 vs. 375.2 m) and 5XSST (mean 21.6 vs. 18.6 s); US patients performed better on the 3TUG test (mean 40.2 vs. 45.0 s). The RePOWER registry provided data on patients with genetically confirmed PMM, thereby improving our understanding of PMM diagnosis and treatment and the differences in global mitochondrial clinical practice.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Founder Allele in SGCG Combining Missense Variant and Multi-Exon Duplication in Turkish Patients With Sarcoglycanopathy. 土耳其肌糖病患者SGCG的一个创始等位基因，结合错义变异和多外显子重复。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-10 DOI: 10.1111/cge.70041

Abdullah Sezer, Afife Büke, Hasan Hüseyin Kazan, Ahmet Kablan, Mustafa Tarık Alay, Beril Talim, Deniz Yüksel, Hanife Saat

{"title":"A Founder Allele in SGCG Combining Missense Variant and Multi-Exon Duplication in Turkish Patients With Sarcoglycanopathy.","authors":"Abdullah Sezer, Afife Büke, Hasan Hüseyin Kazan, Ahmet Kablan, Mustafa Tarık Alay, Beril Talim, Deniz Yüksel, Hanife Saat","doi":"10.1111/cge.70041","DOIUrl":"https://doi.org/10.1111/cge.70041","url":null,"abstract":"Sarcoglycanopathies are autosomal recessive muscular dystrophies characterized by progressive muscle weakness and represent a major subset of limb-girdle muscular dystrophies (LGMDs). They result from pathogenic variants in sarcoglycan genes (SGCA, SGCB, SGCD, and SGCG), which encode subunits of a tetrameric transmembrane complex that stabilizes the dystrophin-associated glycoprotein complex. Among these, SGCG is commonly affected and is associated with LGMD2C/R5. Several founder variants in SGCG have been reported across different populations. Here, we describe a novel founder allele in the Turkish population, comprising a missense variant (c.392A>G, p.Lys131Arg) and a copy number gain (exon 1-4 duplication) that occurs in cis. Through an inductive screening strategy, we identified these linked variants in 11 individuals: five affected patients from four families and six unrelated incidental carriers. Haplotype analysis confirmed a shared genomic background supporting a founder effect. Affected individuals carried the allele in a homozygous or compound heterozygous state with other pathogenic SGCG variants. Molecular and histopathological investigations revealed that the duplicated allele results in mRNA decay and loss of SGCG protein expression. This study represents the first report of a disease-associated duplication in SGCG, highlighting a novel founder allele composed of two linked variants that contribute to sarcoglycanopathy in a specific population.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0