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":"<p><p>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.</p>","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}
{"title":"CAMTA1 Nonsense Variant Inherited From Asymptomatic Mother: Extremely Variable Expressivity in Congenital Ataxia.","authors":"So Young Lee, Jun Hwan Choi, Hyun Jung Lee","doi":"10.1111/cge.70065","DOIUrl":"https://doi.org/10.1111/cge.70065","url":null,"abstract":"<p><p>Complete absence of symptoms in a mother carrying CAMTA1 c.1544C>A contrasts with severe congenital ataxia in her son. Early intervention at 16 months led to exceptional recovery (GMFM-88: 56.5% → 96%), demonstrating unprecedented intrafamilial variability and neuroplasticity potential in CAMTA1-related disorders.</p>","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":"145022935","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
Malik Ali Asghar, Rukhsana Nazir, Saima Siddiqi, Noor Ul Ain
{"title":"Biallelic Variant in SLC6A17 in a Pakistani Family With Autosomal Recessive Intellectual Disability.","authors":"Malik Ali Asghar, Rukhsana Nazir, Saima Siddiqi, Noor Ul Ain","doi":"10.1111/cge.70055","DOIUrl":"10.1111/cge.70055","url":null,"abstract":"<p><p>Autosomal recessive intellectual disability affects 1%-33% of the general population and is a major concern in countries where consanguineous marriages are common. Mental retardation autosomal recessive 48 (MRT 48) (OMIM 616269) is a recessive syndromic disorder characterized by progressive tremors, speech impairment, and behavioral problems. In the present study, we highlight a family with a case of MRT 48. The index patient was second born to healthy consanguineous parents with a history of intellectual disability. Whole exome sequencing of the patient was performed, which revealed a homozygous c.1693T>C;p.(Tyr565His) variant in the SLC6A17 gene. The variant segregated in the extended family with the phenotype. This study broadens the genotypic spectrum of SLC6A17 variants.</p>","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":"144945259","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}
{"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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
Ali Babazade, Taha Enes Cetin, Ozant Helvacı, Ozden Seckin, Gulsum Kayhan
{"title":"Adult-Onset Nephrotic Syndrome due to a Homozygous TNS2 Truncating Variant: Broadening the Mutational Spectrum.","authors":"Ali Babazade, Taha Enes Cetin, Ozant Helvacı, Ozden Seckin, Gulsum Kayhan","doi":"10.1111/cge.70053","DOIUrl":"https://doi.org/10.1111/cge.70053","url":null,"abstract":"<p><p>TNS2-related Nephrotic Syndrome (TNS2-NS) is a rare form of nephrotic syndrome inherited in an autosomal recessive manner, caused by pathogenic variants in the TNS2 gene. Only five cases have been documented, all involving biallelic missense variants with symptoms appearing in early childhood. We describe a 34-year-old man with nephrotic syndrome who was found to have a homozygous stop-gain mutation in TNS2 via exome sequencing. This is the first reported human case with a truncating TNS2 variant and adult-onset disease, differing from earlier cases with early onset and missense mutations. While studies in mice show that Tns2 is vital for kidney health, similar human data are lacking. Our results indicate that null mutations in TNS2 could also lead to nephrotic syndrome and may result in the disease manifesting later in life.</p>","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":"144945244","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}