Clinical Genetics最新文献

{"title":"Generation and Auditory Phenotypic Characterization of Prps1 p.Ala87Thr Mouse Knock-In Model for Human DFNX1 Deafness","authors":"Denise Yan,&nbsp;M'hamed Grati,&nbsp;Rahul Mittal,&nbsp;Yi-Zhou Quan,&nbsp;Wan Du,&nbsp;Zheng-Yi Chen,&nbsp;Xue Zhong Liu","doi":"10.1111/cge.14776","DOIUrl":"10.1111/cge.14776","url":null,"abstract":"<p>Variants in the phosphoribosylpyrophosphate synthetase (<i>PRPS1</i>) gene have been shown to cause X-linked nonsyndromic hearing loss (HL) (DFNX1) in humans. A c.259G&gt;A transition in <i>PRPS1</i>, which leads to p.Ala87Thr, has been demonstrated to cause HL. The aim of this study was to generate a transgenic knock-in (KI) mouse with the Prps1 missense variant p.Ala87Thr and to study its impact on the auditory phenotype. Compared to wild-type (WT) control, transgenic <i>Prps1</i> KI mice started to exhibit HL at 32 kHz at 4–12 weeks of age, with HL extending to 8 and 16 kHz by 48 weeks of age. A significant decrease in the number of hair cells and spiral ganglion neuron (SGN) counts was observed at 48 weeks of age in transgenic KI mice. These traits may be associated with the Bak-dependent mitochondrial apoptosis program, which is triggered by oxidative stress and has been identified as a key mechanism of age-related HL in C57BL/6J mice. Enzymatic assay showed a significant reduction in Prps1 enzymatic activity in KI compared to WT animals. The Prps1 p.Ala87Thr KI mouse model will serve as a valuable tool for developing therapeutic strategies to mitigate HL associated with <i>PRPS1</i> variants.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"566-575"},"PeriodicalIF":2.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14776","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges.","authors":"Guotong Li, Shushu Zhou, Yuqian Li, Sana Atta, Xun Xia, Xuan Sha, Rong Hua, Ping Zhou, Zhaolian Wei, Yunxia Cao, Huan Wu","doi":"10.1111/cge.14783","DOIUrl":"https://doi.org/10.1111/cge.14783","url":null,"abstract":"<p><p>Intercellular bridges (ICBs) are critical in intercellular communication, coordinated cellular development, and the equilibration of cytoplasmic contents between germ cells during vertebrate spermatogenesis. Mammalian TEX14 is specifically expressed in the testes and is a pivotal component of ICBs. It is indispensable for proper spermatogenesis; its deficiency causes meiotic arrest at the pachytene stage of meiotic prophase I, resulting in male infertility with non-obstructive azoospermia (NOA) in murine models. However, the specific effects of TEX14 deficiency on spermatogenesis remain poorly understood. In this study, we identified a novel compound heterozygous mutation in TEX14 (c.802A>T, p.S268C and c.1021C>T, p.R341*) in a patient with NOA. Functional analyses demonstrated that these mutations disrupted TEX14 synthesis. This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations. Our findings provide robust evidence that pathogenic biallelic TEX14 mutations are recurrent genetic etiologies of NOA in humans.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257498","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":"Beyond Carrier Status: CFTR Heterozygosity as an Overlooked Clinical Risk Factor for Pancreatitis.","authors":"Lucas D Richter, Douglas M Ruderfer, Josh F Peterson, Lisa A Bastarache","doi":"10.1111/cge.14780","DOIUrl":"https://doi.org/10.1111/cge.14780","url":null,"abstract":"<p><p>This study assessed the effect of CFTR pathogenic variant status, detected during prenatal carrier screening, for the incidence and clinical recognition of cystic fibrosis-related phenotypes. Data were queried from the Vanderbilt University Medical Center clinical genetic database (CGdb), which includes clinically reported pathogenic variants and electronic health records (EHRs) from 2001 to 2023. Based on carrier screening results, we identified individuals heterozygous for a pathogenic CFTR variant and those who tested negative. Logistic regression tested associations between CFTR carrier status and 11 cystic fibrosis (CF)-related phenotypes. A phenome-wide association study (PheWAS) was performed to identify additional phenotypic associations, and manual chart review was conducted to evaluate recognition and clinical application of CFTR carrier status in patients diagnosed with pancreatitis. Among 12,082 women tested, CFTR carriers (n = 451) were at significantly higher risk of developing acute pancreatitis (p = 3.93 × 10^-6; OR = 4.68 [2.43-9.00]). No other CF-related phenotypes were significantly associated in this female cohort. Manual chart review revealed that CFTR carrier screening results were not clinically correlated with pancreatitis diagnoses. In this large cohort of women tested for prenatal carrier screening, CFTR pathogenic variants relevant to pancreatitis were overlooked, despite informing etiology, management, and prognosis.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224563","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":"A Novel Skeletal Dysplasia With Premaxilla Overgrowth, Gingival Hyperplasia, and Dental Hypercementosis.","authors":"Paulo Marcio Yamaguti, Shélida Vasconcelos Braz, Audrey Asselin, André Ferreira Leite, Caroline Lourenço de Lima, Daniel Rocha de Carvalho, Heliana Dantas Mestrinho, Paulo Tadeu Figueiredo, Guilherme Santos, Nathalia de Aguiar Montenegro, Nunthawan Nowwarote, Benjamin Philippe Jacques Fournier, Muriel de La Dure-Molla, Ariane Berdal, Luiz Claudio Gonçalves de Castro, Neysa Aparecida Tinoco Regattieri, Juliana Forte Mazzeu, Juliane Isaac, Ana Carolina Acevedo","doi":"10.1111/cge.14779","DOIUrl":"https://doi.org/10.1111/cge.14779","url":null,"abstract":"<p><p>This study reports a skeletal disorder marked by facial dysmorphism and a distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis. Whole-exome sequencing identified a homozygous missense variant in ENPP5 (c.173G>T; p.Gly58Val), affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts. RT-qPCR confirmed region-specific expression, with higher Enpp5 expression in premaxillary-maxillary bones compared to the tibia, suggesting site-dependent functional roles. This report links, for the first time, a biallelic ENPP5 variant to a novel syndrome involving premaxillary development, bone and cementum growth, highlighting the need for further functional and clinical investigation.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207839","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":"Mucopolysaccharidosis Type IIIB With Pancytopenia: A Case Report and Hematological Correlations in Mice","authors":"Éliane Beauregard-Lacroix,&nbsp;Patricia Dubot,&nbsp;Alexey V. Pshezhetsky,&nbsp;Philippe M. Campeau","doi":"10.1111/cge.14773","DOIUrl":"10.1111/cge.14773","url":null,"abstract":"<p>Mucopolysaccharidosis type IIIB (MPS IIIB), also called Sanfilippo syndrome B, is a lysosomal storage disease caused by abnormal degradation of heparan sulfate. It is characterized by progressive neurological deterioration with developmental regression and behavioral abnormalities. Additional clinical manifestations can include musculoskeletal anomalies, hearing loss, respiratory tract anomalies, and cardiovascular disease. Here, we report a second individual with MPS IIIB and chronic pancytopenia. To support our hypothesis of a pathophysiological relationship between these clinical findings, we performed hematological studies in MPS IIIB ^{\u0000 <i>Naglu−/−</i>\u0000} mice, which revealed a microcytic anemia as well as a decreased monocyte count, without thrombocytopenia. Hematological findings are thought to be secondary to MPS IIIB even though the exact pathophysiological mechanism remains to be determined. Although it likely represents an uncommon clinical feature, we suggest that complete blood count should be considered as part of the clinical surveillance for individuals with MPS IIIB.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"604-608"},"PeriodicalIF":2.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14773","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell Motility.","authors":"María Eugenia Amato, Marcos Frías, Alfredo Cerisola, Mònica Roldán, Juan Darío Ortigoza-Escobar","doi":"10.1111/cge.14774","DOIUrl":"https://doi.org/10.1111/cge.14774","url":null,"abstract":"<p><p>CYFIP2, essential for actin cytoskeleton regulation, is implicated in early-onset developmental and epileptic encephalopathy (DEE) with neurodevelopmental impairments and variable movement disorders, including occasional dyskinetic crises. We report a novel CYFIP2 frameshift variant (c.281_282insA/p.(Gln95ProfsTer15)) causing dyskinetic crises and to assess its functional impact. Clinical and genetic evaluations were conducted, alongside functional studies using patient-derived fibroblasts. Actin dynamics and cell motility were analyzed with confocal microscopy and live-cell imaging. The patient exhibited DEE, delayed neurodevelopment, refractory seizures, and movement disorders, including dystonia, choreoathetosis, and dyskinetic crises. Functional studies revealed disrupted actin organization, impaired cell motility, and altered protrusive structures. This study confirms CYFIP2 as a cause of dyskinetic crises and underscores its role in cellular dynamics, broadening the phenotypic spectrum of CYFIP2-related disorders. Early genetic diagnosis and further research are essential to developing targeted therapeutic strategies.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157204","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":"ACTC1 Variants Result in Isolated and Syndromic Cardiac Phenotypes.","authors":"Yuri A Zarate, Lina Abdelmoti, Seungjae Oh, Andreya White, Cassandra Starks, Margaret G Au, Jing Chen, Nicole K Weaver, Konstantin V Korotkov, Emilia Galperin","doi":"10.1111/cge.14775","DOIUrl":"10.1111/cge.14775","url":null,"abstract":"<p><p>Individuals carrying pathogenic variants in ACTC1 present with several cardiac phenotypes, including hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular noncompaction cardiomyopathy. In the current work, we expand the clinical and genetic spectrum of phenotypes caused by ACTC1 genetic variants by describing two individuals with heterozygous variants involving residues Gly57 or Glu101. These individuals presented with facial dysmorphism, short stature, and skeletal anomalies in addition to hypertrophic and left ventricular noncompaction cardiomyopathies. Protein structure analysis showed these variants alter the ATP binding or putative protein-protein interactions, while in vivo zebrafish analysis validated the pathogenicity of these ACTC1 variants and their impact on the development of the cranial tissues. Combined with recent reports of other individuals with ACTC1 variants and extracardiac phenotypes, this study provides further evidence of the extensive molecular and clinical diversity related to ACTC1.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA Analysis Enables Resolution and Reclassification of Reportedly Benign Synonymous Variants","authors":"Adina Fuchs,&nbsp;Inbar Kobal,&nbsp;Dov Popper,&nbsp;Shay Porat,&nbsp;Joshua I. Rosenbloom,&nbsp;Mordechai Slae,&nbsp;Shira Yanovsky Dagan,&nbsp;Vardiella Meiner,&nbsp;Vered Molho-Pessach,&nbsp;Hagit Daum,&nbsp;Tamar Harel","doi":"10.1111/cge.14772","DOIUrl":"10.1111/cge.14772","url":null,"abstract":"<p>Synonymous variants can significantly impact protein levels and function, particularly through alterations in RNA processing. Consequently, variant classification must consider the broader impact on RNA splicing. We present three cases where synonymous variants were detected through exome sequencing. The variants in <i>LARS1</i> and <i>POLE</i> were located at the last nucleotide of the exon (i.e., splice donor site), while the <i>COL2A1</i> variant was located three nucleotides downstream of the splice acceptor site. Two variants were previously classified in ClinVar as “likely benign.” Segregation analysis confirmed segregation of the variants with the phenotype in available family members, and RNA studies revealed exon skipping in conserved regions of the protein, leading to reclassification of these variants as “likely pathogenic” and ultimately improving clinical management. These findings highlight the importance of incorporating RNA-based testing to directly evaluate splicing effects and demonstrate the critical role of RNA analysis in the accurate interpretation of variants and their implications for diagnosis and treatment.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"599-603"},"PeriodicalIF":2.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14772","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Neurodevelopmental Characteristics of Paralogous Gain-of-Function Variants at GRIA2 p.Gly792 and GRIA3 p.Gly803","authors":"Emilie Sjøstrøm,&nbsp;Dorota Studniarczyk,&nbsp;Xinyao Dou,&nbsp;Rebekka S. Dahl,&nbsp;Vincent Cruz,&nbsp;Heng Wang,&nbsp;Sandra Mercier,&nbsp;Wallid Deb,&nbsp;Thomas Besnard,&nbsp;Jennifer Friedman,&nbsp;Miriam Essid,&nbsp;Sana Karoui,&nbsp;Lamia Ben Jemaa,&nbsp;Thouraya Benyounes,&nbsp;Gaetan Lesca,&nbsp;Davide Tonduti,&nbsp;Maria Iascone,&nbsp;Simona Orcesi,&nbsp;Melanie Fradin,&nbsp;Christèle Dubourg,&nbsp;Silvia Napuri,&nbsp;Stuart G. Cull-Candy,&nbsp;Ian D. Coombs,&nbsp;Mark Farrant,&nbsp;Allan Bayat","doi":"10.1111/cge.14770","DOIUrl":"10.1111/cge.14770","url":null,"abstract":"<p>GRIA-related disorders arise from disease-causing variants in <i>GRIA1</i>, <i>GRIA2</i>, <i>GRIA3</i>, or <i>GRIA4</i> that encode α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs). Rare monoallelic <i>GRIA1–4</i> variants affecting AMPAR function can potentially lead to neurodevelopmental disorders. The impact on AMPAR function may manifest as either gain-of-function (GOF) or loss-of-function (LOF). We recruited nine unrelated patients with either known disease-causing GOF variants in <i>GRIA3</i> at position p.Gly803 or variants at the paralogous position in <i>GRIA2</i> (p.Gly792). Specifically, five patients carried a de novo <i>GRIA3</i> variant (p.Gly803Glu or p.Gly803Val), one carried a maternally inherited <i>GRIA3</i> variant (p.Gly803Ala) and three carried de novo <i>GRIA2</i> variants (p.Gly792Arg, p.Gly792Val, or p.Gly792Glu) which we demonstrate are also GOF. Recurrent symptoms included developmental delay affecting both motor skills and language abilities; cognitive impairment; behavioral and psychiatric comorbidities; hypertonia, cerebral palsy, non-epileptic myoclonus, and treatment-resistant epilepsy. We also provide insights into social skills, levels of autonomy, living arrangements, and educational attainment. We compared the clinical features associated with the two paralogous GOF <i>GRIA2</i> and <i>GRIA3</i> variants. Our study elucidates the developmental aspects, cognitive abilities, seizure profiles, and behavioral challenges associated with these variants and contributes to advancing our understanding and treatment of patients affected by this rare condition.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"553-565"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel TAF1C Missense Variant Causes Neurodevelopmental Regression via Disrupted Nucleolar Localization and Nucleoplasmic Aggregation","authors":"S. Rehan Ahmad,&nbsp;Natchimuthu Vijayakumar,&nbsp;Nazim Nasir","doi":"10.1111/cge.14771","DOIUrl":"10.1111/cge.14771","url":null,"abstract":"<div>\u0000 \u0000 <p>TAF1C (TATA box-binding protein-associated factor, RNA polymerase I subunit C) is an essential component of the RNA polymerase I transcription machinery responsible for ribosomal RNA synthesis and nucleolar function. Variants in <i>TAF1C</i> have recently emerged as rare genetic causes of early-onset neurological syndromes characterized by nucleolar stress and impaired ribosome biogenesis, leading to developmental delay and brain atrophy. Here, we report a novel homozygous missense variant (c.1766C&gt;T; p.Ser589Leu) in <i>TAF1C</i> in a 3-year 8-month-old boy who exhibited normal development until age two, followed by generalized seizures and progressive neurodevelopmental regression, spasticity, microcephaly, and cerebellar atrophy. MRI revealed asymmetric diffusion restriction and diffuse cerebellar atrophy. Although the mutant <i>TAF1C</i> transcript and protein were expressed at normal levels in peripheral blood cells, immunofluorescence analysis revealed a loss of nucleolar localization and the formation of abnormal thread-like aggregates within the nucleoplasm. These findings suggest that the p.Ser589Leu variant causes disease through functional mislocalization rather than loss of expression. Our case expands the phenotypic and mechanistic spectrum of <i>TAF1C</i>-related disorders and highlights the importance of proper subnuclear localization for maintaining neuronal function and development.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"594-598"},"PeriodicalIF":2.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074965","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}