Clinical Genetics最新文献

{"title":"Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum.","authors":"Tarik Duzenli, Vusala Yusufova, Huriye Cetin, Esra Serdaroglu, Bahar Buyukkaragoz, Gulsum Kayhan","doi":"10.1111/cge.70009","DOIUrl":"https://doi.org/10.1111/cge.70009","url":null,"abstract":"<p><p>Spastic paraplegia 90 (SPG90; OMIM #620416, 620417) is a rare neurologic disease caused by monoallelic or biallelic variants in the serine palmitoyltransferase small subunit A (SPTSSA) gene. This syndrome is characterized by neurodevelopmental delay, sensorineural hearing loss, progressive motor impairment, and lower extremity spasticity. To date, only three patients have been reported. In this report, we present a 10-year-old female patient with global developmental delay, inability to walk, axial hypotonia, extremity spasticity, dystonia, distal renal tubular acidosis, recurrent urinary tract infections, nephrolithiasis, neurogenic bladder, and primary polydipsia. Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome. The neurogenic bladder and primary polydipsia found in our patient are novel findings, and we propose that genitourinary problems may be a component of the syndrome.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324629","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":"Diagnostic Yield and Clinical Impact of a Small Genetic Panel for Kidney Disease: A Multicenter, Retrospective European Study.","authors":"Silvia Giovanella, Antonio Miguel Poyatos-Andújar, Maria Mar Aguila Garcia, Almudena Avila-Fernandez, Ana Bustamante-Aragonés, Carmen Ayuso, Antonio Percesepe, Davide Martorana, Maria Ferri, Alessandra Terracciano, Laura Massella, Johanna Chester, Francesca Testa, Giulia Ligabue, Marco Ferrarini, Dino Gibertoni, Gaetano Alfano, Elena Tenedini, Lucia Artuso, Marco Marino, Olga Calabrese, Enrico Tagliafico, Riccardo Magistroni","doi":"10.1111/cge.70002","DOIUrl":"https://doi.org/10.1111/cge.70002","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) has a genetic origin in 10% of patients. The most effective and cost-beneficial genetic testing methodology is debated. A multicenter, retrospective analysis of 692 patients with panel genetic testing (44 genes) evaluated the diagnostic yield, independent predictors of genetic diagnoses, and clinical impact. Diagnostic variants identified totaled 252, resulting in a 36% yield. The highest yields were associated with cystic disease (49%). No diagnostic variants were identified in unknown CKD. Independent clinical predictors of diagnosis were clinical presentation, family history, and early disease onset. Genetic diagnoses confirmed clinical suspicion in 70%, defined the diagnosis in 23%, and altered clinical diagnosis in 7%. Despite study limitations, a 44 gene panel seems to have a similar diagnostic yield as larger panels and whole-exome sequencing (WES) approaches. Patient selection based on independent predictors of genetic diagnosis may further increase diagnostic yield and cost-effectiveness, especially useful in cost-restricted contexts.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324628","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":"Genetic and Structural Variations in Czech Patients With Congenital Myopathies.","authors":"Jana Zídková, Barbora Lauerová, Lívie Mensová, Tereza Kramářová, Johana Kopčilová, Kamila Réblová, Magdaléna Soukup Vodičková, Martina Hujňáková, Jana Haberlová, Marie Rohlenová, Radim Mazanec, Jana Šoukalová, Renata Gaillyová, Emílie Vyhnálková, Miroslava Balaščaková, Pavlína Danhofer, Lenka Juříková, Dagmar Grečmalová, Andrea Gřegořová, Pavlína Plevová, Martina Langová, Tomáš Honzík, Martin Magner, Martina Klincová, Pavla Solařová, Mária Šenkeříková, Lenka Fajkusová","doi":"10.1111/cge.14782","DOIUrl":"https://doi.org/10.1111/cge.14782","url":null,"abstract":"<p><p>Congenital myopathies (CMs) are a heterogeneous group of genetic muscle disorders characterized by hypotonia and muscle weakness, with pathogenic variants identified in at least 41 genes and inheritance patterns including autosomal dominant (AD), recessive (AR), and X-linked (XL). We present 79 unrelated patients with genetically confirmed CM using next-generation sequencing (NGS). A total of 113 mutant alleles carrying 97 different variants with a presumed pathogenic effect were identified. According to the HGMD database, 54 of these variants have been reported exclusively in the Czech CM population to date. All but five variants were small-scale. Large gene deletions were identified in the MTM1, NEB, and RYR1 genes. Sequencing of breakpoint junctions in the identified NEB and RYR1 deletions provided insights into the upstream mechanisms leading to genomic instability and resulting in structural variations. We present the family with dominant inheritance of the NEB deletion of exons 19-78. We assume that our family represents another reported case of a dominant mutation in the NEB gene. Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316029","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":"Stargardt Disease: Clinical Features and Genotypes in an Indian Cohort.","authors":"Mythri K Rao, Ramya R Nadig, J Syed Ali Fathima Afrin, Sarangapani Sripriya, Porkodi Periasamy, Ramavath Sree Keerti, Muna Bhende","doi":"10.1111/cge.14778","DOIUrl":"https://doi.org/10.1111/cge.14778","url":null,"abstract":"<p><p>In this report, we describe the clinical features and spectrum of gene variants of an Indian cohort with Stargardt disease (STGD). We reviewed the medical records of 98 eyes of 49 patients with STGD who underwent colour fundus photography, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), full-field electroretinography (FFERG) and genetic testing using an NGS panel. Demographic data, clinical features, FAF, OCT, FFERG characteristics, and genotype analysis were the main outcome measures. The median age at onset and presentation was when the patients were 14 years (Range: 5-49 years) and 22 years (Range: 6-55 years) old, respectively. Median BCVA was 0.7 logMAR (Range: 0-1.8 logMAR). Lower BCVA was associated with the presence of flecks outside the arcade, significantly lower central foveal thickness (CFT), reduced scotopic and photopic FFERG response (Type III) and multiple areas of low FAF signal at the posterior pole with a heterogeneous background (Type III). Longer disease duration was associated with Type III FAF signal and Type III ERG response. ABCA4 gene mutation was seen in 44 (> 80%) patients; 1 each had PROM1, CNGB3, and PDE6A/TULP1 variants, and 2 had no known variants. Later onset of the disease was noted in patients with 2 recurrent variants (c.5882G>A and c.859-9T>C) detected in 8 patients each. Most patients reported at a younger age compared to other populations. FAF categories, CFT, and FFERG patterns correlated with disease duration and BCVA.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301222","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":"Diagnosis of Angelman Syndrome, With 66 Years of Delay, Using Hypothesis-Free DNA Methylation Profiling","authors":"Mathis Hildonen,&nbsp;Marco Ferilli,&nbsp;Ilona Krey,&nbsp;Oona Kohnen,&nbsp;Camilla Cappelletti,&nbsp;Konrad Platzer,&nbsp;Andrea Ciolfi,&nbsp;Rami Abou Jamra,&nbsp;Marco Tartaglia,&nbsp;Zeynep Tümer","doi":"10.1111/cge.70000","DOIUrl":"10.1111/cge.70000","url":null,"abstract":"<p>Hypothesis-free DNA methylation profiling in a 66-year-old male with unexplained neurodevelopmental disorder enabled the exclusion of <i>ZNF142</i>-related disease (left panel) and led to a retrospective diagnosis of Angelman syndrome, highlighting the diagnostic potential of single-patient epigenetic screening (right panel).\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 3","pages":"369-370"},"PeriodicalIF":2.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301220","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":"First Report of a Novel Pathogenic Variant in the RREB1 Gene Associated With Obesity and Metabolic Syndrome.","authors":"Nurana Mammadova, A Baki Yildirim, Nihal Hatipoglu, Munis Dundar","doi":"10.1111/cge.70001","DOIUrl":"https://doi.org/10.1111/cge.70001","url":null,"abstract":"<p><p>Ras-responsive element binding protein 1 (RREB1) is a zinc finger transcription factor that is crucial in regulating cell growth, gene expression, and DNA repair. It functions as both a repressor and an activator, with its activity controlled by the MAPK signaling pathway. RREB1 has been implicated in various conditions such as type 2 diabetes (T2D), obesity, and cancer, suggesting its potential as both a biomarker and a therapeutic target for these diseases. While several cases of 6p terminal deletions in the RREB1 gene and one case of Noonan-like RASopathy due to a loss-of-function variant have been reported, this study presents the first case of a pathogenic loss-of-function variant in RREB1 associated with morbid obesity and metabolic disturbances. Our patient, a 16-year-old male, exhibited morbid obesity, metabolic disorders, moderate intellectual disability, and atypical autism symptoms. He was referred to our clinic by the pediatric endocrinology department for genetic evaluation. Initial genetic testing included karyotype analysis and SNP array testing with 700 000 probes. Whole exome sequencing (WES) was then performed on the patient and his family, revealing a de novo novel variant, c.3178_3179del, p.(Glu1060Argfs*37) in the RREB1 gene, which was confirmed by Sanger sequencing. This novel variant underscores the critical role of RREB1 in regulating metabolic processes, particularly obesity. Additionally, the patient's neurodevelopmental delay aligns with previously reported findings of RREB1 loss-of-function variants. These results highlight the need for further research to fully understand the metabolic implications of RREB1 gene loss, with this study providing valuable insights for future investigations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301221","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":"Clinical and Molecular Characterization of Xia-Gibbs Syndrome: Expanding the Phenotypic Spectrum in a Brazilian Cohort.","authors":"Maísa Ganz Sanchez Sennes, Laura Machado Lara Carvalho, Matheus Augusto Araújo Castro, Giovana Manilli Toccoli, Sofia de Oliveira Farias, Davi Mendes Campo Fialho, Eny Maria Goloni Bertollo, Erika Cristina Pavarino, Larissa Sampaio de Athayde, Cecilia Barbosa Buck, Maria Betânia Pereira Toralles, Maria Isabel Melaragno, Mariluce Riegel-Giugliani, Gustavo Marquezani Spolador, Paulo Alberto Otto, Caroline Brandão Piai, Fernando Kok, Ceres Schmitz Cechella, Carla Rosenberg, Juan Clinton Llerena, Débora Romeo Bertola, Salmo Raskin, Chong Ae Kim, Ana Cristina Victorino Krepischi","doi":"10.1111/cge.14777","DOIUrl":"https://doi.org/10.1111/cge.14777","url":null,"abstract":"<p><p>Xia-Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians. Genomic variants and their segregation were validated via Sanger sequencing. Statistical analyses were conducted to evaluate genotype-phenotype associations. Twelve novel AHDC1 causative variants were documented. ID, hypotonia, motor developmental delay, and varied nonspecific facial dysmorphisms were observed in all patients, while speech impairment and autism spectrum disorder were present in nearly all. Three frequent phenotypes, not previously reported, were identified: hyperphagia/food obsession, genital/gonadal alterations in males, and shortening of the Achilles tendon. Additionally, our findings provide statistically significant support for previously reported genotype-phenotype associations between pathogenic variants in the first half of the AHDC1 coding region and the occurrence of epilepsy and scoliosis. We also propose a novel association between N-terminal variants and developmental regression. In summary, our results broaden the clinical phenotype of XGS, with musculoskeletal and genital/gonadal abnormalities highlighting the multisystem involvement in this condition, beyond neurodevelopmental deficits. Comprehensive phenotypic assessments in all identified XGS cases are recommended to accurately recognize and associate novel clinical signs with XGS.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274305","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":"Generation and Auditory Phenotypic Characterization of Prps1 p.Ala87Thr Mouse Knock-In Model for Human DFNX1 Deafness.","authors":"Denise Yan, M'hamed Grati, Rahul Mittal, Yi-Zhou Quan, Wan Du, Zheng-Yi Chen, Xue Zhong Liu","doi":"10.1111/cge.14776","DOIUrl":"https://doi.org/10.1111/cge.14776","url":null,"abstract":"<p><p>Variants in the phosphoribosylpyrophosphate synthetase (PRPS1) gene have been shown to cause X-linked nonsyndromic hearing loss (HL) (DFNX1) in humans. A c.259G>A transition in PRPS1, 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 Prps1 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 PRPS1 variants.</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":"144265468","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 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}