Clinical Genetics最新文献_第4页

LONP1 Variants Are Associated With Clinically Diverse Phenotypes. LONP1变异与临床多样化表型相关。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-10 DOI: 10.1111/cge.70057

Randee E Young, Lu Qiao, Rebecca Hernan, David A Sweetser, Jessica L Waxler, Daryl A Scott, Tiana M Scott, Seema R Lalani, Mahshid S Azamian, Jill A Rosenfeld, Bret Bostwick, Lindsay C Burrage, Lance H Rodan, Bianca E Russell, Marina Dutra-Clarke, Michael Kruer, Somayeh Bakhtiarim, Hossein Darvish, David J Amor, Shamima Rahman, Karen Stals, Lisa Bradley, Susan Byrne, Leandra K Tolusso, Beatrix Wong, Laura Benedict, Kimberly Wallis, Kestutis Micke, Cindy Colson, Thomas Smol, Sabrina V Southwick, Kristen A Miller, Michelle L Kush, Odelia Chorin, Annick Rothschild, Wei Wang, Yufeng Shen, Wendy K Chung

{"title":"LONP1 Variants Are Associated With Clinically Diverse Phenotypes.","authors":"Randee E Young, Lu Qiao, Rebecca Hernan, David A Sweetser, Jessica L Waxler, Daryl A Scott, Tiana M Scott, Seema R Lalani, Mahshid S Azamian, Jill A Rosenfeld, Bret Bostwick, Lindsay C Burrage, Lance H Rodan, Bianca E Russell, Marina Dutra-Clarke, Michael Kruer, Somayeh Bakhtiarim, Hossein Darvish, David J Amor, Shamima Rahman, Karen Stals, Lisa Bradley, Susan Byrne, Leandra K Tolusso, Beatrix Wong, Laura Benedict, Kimberly Wallis, Kestutis Micke, Cindy Colson, Thomas Smol, Sabrina V Southwick, Kristen A Miller, Michelle L Kush, Odelia Chorin, Annick Rothschild, Wei Wang, Yufeng Shen, Wendy K Chung","doi":"10.1111/cge.70057","DOIUrl":"https://doi.org/10.1111/cge.70057","url":null,"abstract":"LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032774","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

CAMTA1 Nonsense Variant Inherited From Asymptomatic Mother: Extremely Variable Expressivity in Congenital Ataxia. 从无症状母亲遗传的CAMTA1无意义变异：先天性共济失调的极端可变表达。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-08 DOI: 10.1111/cge.70065

So Young Lee, Jun Hwan Choi, Hyun Jung Lee

引用次数: 0

A Novel Homozygous Nonsense Pathogenic Variant of the CPAMD8 Gene Associated With Congenital Microcoria. 与先天性小冠相关的camd8基因的一种新的纯合无义致病变异。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-08 DOI: 10.1111/cge.70067

Jing-Fan Gao, Xin Jin, Jing-Rao Wang, Shu Wang, Hong Zhang

{"title":"A Novel Homozygous Nonsense Pathogenic Variant of the CPAMD8 Gene Associated With Congenital Microcoria.","authors":"Jing-Fan Gao, Xin Jin, Jing-Rao Wang, Shu Wang, Hong Zhang","doi":"10.1111/cge.70067","DOIUrl":"https://doi.org/10.1111/cge.70067","url":null,"abstract":"Congenital microcoria (MCOR) is a rare inherited ocular disorder. Here, we describe a novel nonsense variant in the CPAMD8 gene in a patient with MCOR. We conducted a comprehensive clinical examination of a patient diagnosed with MCOR and performed whole-exome sequencing to identify potential pathogenic variants. Additionally, bioinformatics prediction tools were employed to assess the impact of the identified variant on protein structure and function. The patient presented with hallmark features of MCOR, such as bilaterally constricted pupils and a poor response to mydriatic agents. A novel homozygous nonsense variant, c.2679C>G (p.Tyr893*), was identified in the CPAMD8 gene. Protein modeling revealed that the variant results in complete truncation of the C-terminal domain of CPAMD8, disrupting its functional domains and potentially affecting its biological activity. Furthermore, electrostatic potential energy analysis demonstrated increased surface asymmetry of the protein, suggesting that the variant may interfere with protein-molecule interactions. Previous studies have suggested a strong association between MCOR and deletions in the 13q32.1 region of chromosome 13; however, the specific pathogenic genes involved have remained unclear. In this study, we show that the nonsense variant c.2679C>G (p.Tyr893*) in CPAMD8 is associated with MCOR, providing new insights into the genetic basis of the disease.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022959","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

Identification of BCL2L11 as a Candidate Gene for Hereditary Predisposition to Non-Medullary Thyroid Cancer Using Familial Whole-Exome-Sequencing. 利用家族性全外显子组测序鉴定BCL2L11作为非髓样甲状腺癌遗传易感的候选基因

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-03 DOI: 10.1111/cge.70060

Duygu Abbasoglu, Mathis Lepage, Nicolas Sonnier, Sandrine Viala, Nancy Uhrhammer, Flora Ponelle-Chachuat, Anne Cayre, Maud Privat, Mathias Cavaillé, Yannick Bidet

{"title":"Identification of BCL2L11 as a Candidate Gene for Hereditary Predisposition to Non-Medullary Thyroid Cancer Using Familial Whole-Exome-Sequencing.","authors":"Duygu Abbasoglu, Mathis Lepage, Nicolas Sonnier, Sandrine Viala, Nancy Uhrhammer, Flora Ponelle-Chachuat, Anne Cayre, Maud Privat, Mathias Cavaillé, Yannick Bidet","doi":"10.1111/cge.70060","DOIUrl":"https://doi.org/10.1111/cge.70060","url":null,"abstract":"Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, and increased risk of metastasis and recurrence. Although no high penetrance predisposing gene has been identified at present, the estimated contribution of genetics is significant. Our study explored five families presenting FNMTC using Whole-Exome Sequencing and found three candidate genes: TELO2 in one family, UACA and BCL2L11 in another. All of these tumor suppressor genes are expressed in the thyroid, exhibit under-expression in tumor tissue compared to healthy tissue both in silico and in our samples, and two of them are known to be involved in thyroid carcinogenesis via the FOXO3A pathway. Functional analysis to validate these candidate genes in thyroid cancer cells showed that one of the three, BCL2L11, has a tumor suppressor effect on proliferation and apoptosis. Their impact on hereditary predisposition to thyroid cancer, as well as their combined effects, requires further study. Indeed, a case-control study would be essential to determine the diagnostic utility of their routine analysis.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991483","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

Biallelic Variant in SLC6A17 in a Pakistani Family With Autosomal Recessive Intellectual Disability. 巴基斯坦常染色体隐性智力残疾家庭SLC6A17双等位变异

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-02 DOI: 10.1111/cge.70055

Malik Ali Asghar, Rukhsana Nazir, Saima Siddiqi, Noor Ul Ain

引用次数: 0

Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients. MICU1的双等位基因变异导致锥体外系症状的肌病：61例患者的病例系列、表型谱和基因型-表型相关性

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-02 DOI: 10.1111/cge.70062

Pegah Beheshti, Fahimeh Akbarian, Emran Esmaeilzadeh, Hamid Galehdari, Mehdi Khorrami, Sadeq Vallian, Alireza Abdi, Özge Güngör, Rasim Tuncel, Ayca Aykut, Özgul Ekmekci, Haluk Akın, Asude Durmaz, Atefeh Sohanforooshan Moghaddam, Niloofar Chamanrou, Fatemeh Karimi, Arezu Kazemi, Mahvash Habibi, Mohammad Amin Tabatabaiefar, Hamid Reza Khorram Khorshid, Farshid Parvini, Uluç Yiş, Ipek Polat, Leila Youssefian, Hassan Vahidnezhad, Morteza Heidari, Payam Sarraf, Ehsan Ghayoor Karimiani, Reza Maroofian, Sajjad Biglari

{"title":"Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients.","authors":"Pegah Beheshti, Fahimeh Akbarian, Emran Esmaeilzadeh, Hamid Galehdari, Mehdi Khorrami, Sadeq Vallian, Alireza Abdi, Özge Güngör, Rasim Tuncel, Ayca Aykut, Özgul Ekmekci, Haluk Akın, Asude Durmaz, Atefeh Sohanforooshan Moghaddam, Niloofar Chamanrou, Fatemeh Karimi, Arezu Kazemi, Mahvash Habibi, Mohammad Amin Tabatabaiefar, Hamid Reza Khorram Khorshid, Farshid Parvini, Uluç Yiş, Ipek Polat, Leila Youssefian, Hassan Vahidnezhad, Morteza Heidari, Payam Sarraf, Ehsan Ghayoor Karimiani, Reza Maroofian, Sajjad Biglari","doi":"10.1111/cge.70062","DOIUrl":"10.1111/cge.70062","url":null,"abstract":"Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945185","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

Novel Biallelic Variants in DLD Gene Cause a Reversible Sensory Neuropathy. DLD基因的新型双等位变异引起可逆性感觉神经病变。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-01 DOI: 10.1111/cge.70052

Lu Wang, Ying Xiong, Kaiyan Jiang, Dandan Tan, Liya Zhang, Min Zhu, Meihong Zhou, Yusen Qiu, Daojun Hong

{"title":"Novel Biallelic Variants in DLD Gene Cause a Reversible Sensory Neuropathy.","authors":"Lu Wang, Ying Xiong, Kaiyan Jiang, Dandan Tan, Liya Zhang, Min Zhu, Meihong Zhou, Yusen Qiu, Daojun Hong","doi":"10.1111/cge.70052","DOIUrl":"https://doi.org/10.1111/cge.70052","url":null,"abstract":"Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare autosomal recessive disorder that typically affects the liver, brain, and muscle. Peripheral neuropathy has not been previously associated with this condition. We report a novel case of DLDD in a 20-year-old woman who presented with recurrent hepatic dysfunction and progressive sensory neuropathy. Clinical evaluation, electrophysiology, and nerve biopsy revealed a severe sensory axonal neuropathy with lipid accumulation. Genetic analysis identified compound heterozygous DLD variants (c.745G>T, p.G249C; c.1344_1347del, p.D448Efs*16), and Western blotting confirmed markedly reduced DLD protein in patient-derived fibroblasts. Treatment with a branched-chain amino acid (BCAA)-free formula, methylcobalamin, and thiamine led to complete resolution of vomiting and significant improvement in neuropathic symptoms, as confirmed by follow-up nerve conduction studies. This is the first report to link DLDD with a reversible sensory neuropathy, expanding the phenotypic spectrum of the disease. Our findings suggest a role for lipid dysregulation and metabolic imbalance in the pathogenesis of peripheral nerve involvement and support early targeted dietary therapy in patients with atypical DLDD presentations.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945208","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

Phenotype Analysis in Two Families With Otopalatodigital Syndrome Spectrum Disorder Based on FLNA Gene Variants. 基于FLNA基因变异的两家系耳腭指综合征谱系障碍表型分析。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-30 DOI: 10.1111/cge.70056

Martin Schwarz, Miroslav Fišer, Lenka Šodková, Eva Míšová, Martin Drahanský, Tomáš Vokálek, Renata Michalovská, Adéla Matějková, Jaroslava Jindrová, Šárka Bendová, Milan Macek

{"title":"Phenotype Analysis in Two Families With Otopalatodigital Syndrome Spectrum Disorder Based on FLNA Gene Variants.","authors":"Martin Schwarz, Miroslav Fišer, Lenka Šodková, Eva Míšová, Martin Drahanský, Tomáš Vokálek, Renata Michalovská, Adéla Matějková, Jaroslava Jindrová, Šárka Bendová, Milan Macek","doi":"10.1111/cge.70056","DOIUrl":"https://doi.org/10.1111/cge.70056","url":null,"abstract":"Otopalatodigital spectrum disorders (OPDSD), comprising otopalatodigital syndromes types 1 and 2 (OPD1, OPD2) and frontometaphyseal dysplasia (FMD), are rare X-linked disorders caused by FLNA gene variants, with phenotypes ranging from mild skeletal anomalies to severe multisystem malformations. We describe two unrelated cases: a 14-year-old male (P1, FMD) and an aborted fetus (P2, OPD2). Whole-exome sequencing identified hemizygous maternally inherited FLNA gene variants in P1 (c.733G>A; p.Glu245Lys) and P2 (c.3707G>A; p.Gly1236Asp, novel), expanding the OPD2 mutational spectrum (NM_001110556). P1 presented with facial dysmorphism, dental anomalies, flattened thumbs, and dermatoglyphic changes; P2 showed facial dysmorphism, skeletal and cardiac malformations, and omphalocele. These cases underscore the breadth of OPDSD phenotypic variability and add novel genetic data. Dental management demands multidisciplinary care from infancy through adolescence, including cleft repair, orthodontics for micrognathia and facial aesthetics, and treatment of dental anomalies. Early recognition, molecular diagnosis, and coordinated management are critical for improving outcomes in these complex disorders.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945220","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

MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families. MAP1B变异破坏神经元迁移：来自三个新家族的见解。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-28 DOI: 10.1111/cge.70059

Jessica Archer, Matt Edwards, Thomas Macdougall, Anne Baxter, Himanshu Goel

{"title":"MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families.","authors":"Jessica Archer, Matt Edwards, Thomas Macdougall, Anne Baxter, Himanshu Goel","doi":"10.1111/cge.70059","DOIUrl":"https://doi.org/10.1111/cge.70059","url":null,"abstract":"MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as a cause of neurodevelopmental disorders characterized by intellectual disability, epilepsy, and cortical malformations, including periventricular nodular heterotopia (PVNH) and polymicrogyria (PMG). However, the phenotypic and neuroimaging spectrum associated with MAP1B-related disease remains incompletely defined. We describe seven affected individuals from three unrelated families with pathogenic MAP1B variants. Clinical, neuroimaging, and genetic data were analyzed in the context of emerging literature to delineate the pathogenic mechanisms and phenotypic variability associated with MAP1B dysfunction. All individuals carried loss of function MAP1B variants. Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available. These findings reinforce MAP1B's central role in cytoskeletal regulation, neuronal positioning, and synaptic connectivity. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching. Our case series expands the clinical and radiological phenotype associated with MAP1B-related disorders and highlights its position as a key cytoskeletal regulator in human corticogenesis. Systematic genotype-phenotype correlation and functional studies are needed to inform diagnostic interpretation and explore therapeutic avenues in MAP1B-associated disease.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945188","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

Adult-Onset Nephrotic Syndrome due to a Homozygous TNS2 Truncating Variant: Broadening the Mutational Spectrum. 由纯合子TNS2截断变异引起的成人肾病综合征：扩大突变谱。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-08-27 DOI: 10.1111/cge.70053

Ali Babazade, Taha Enes Cetin, Ozant Helvacı, Ozden Seckin, Gulsum Kayhan

引用次数: 0