Clinical Genetics最新文献

{"title":"Clinical Characterization of Patients With 5q Spinal Muscular Atrophy Types 2 and 3 in Brazil: A Cross-Sectional Observational Study.","authors":"Elice Carneiro Batista, Edmar Zanoteli, Henrique Andrade R Fonseca, Graziela Jorge Polido, Jonas Alex Morales Saute, Adriana Banzzatto Ortega, Marcondes Cavalcante França Junior, Acary Souza Bulle Oliveira, Paulo Victor Sgobbi de Souza, Juliana Gurgel Giannetti, André Luiz Santos Pessoa, Alexandra Prufer de Queiroz Campos Araújo, Mário Fritsch Toros Neves, Raquel Tavares Boy da Silva, Frederico Monfardini, Gustavo Prado Dos Santos, Bruna Dos Santos Sampaio, Diogo Fagundes Moia, Fernando Galan Júnior, Luciana Pereira Almeida de Piano, Camila Santos Nascimento de Albuquerque, Flávia Miranda Duarte, Viviane Aparecida Rodrigues Sant'Anna, Mariane Pereira, Jomenica de Bortoli Livramento, Ronaldo Vicente Pereira Soares, Denison Alves Pedrosa, Vanessa Teich, Luiz Vicente Rizzo, Otávio Berwanger, João Brainer Clares de Andrade, Gisele Sampaio Silva","doi":"10.1111/cge.70176","DOIUrl":"https://doi.org/10.1111/cge.70176","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA), linked to chromosome 5q, is a rare hereditary neurodegenerative disease characterized by progressive motor neuron loss. It is classified into subtypes based on age at onset and the highest motor milestone achieved. This cross-sectional observational study aimed to describe the clinical profile of patients with types 2 and 3 SMA followed within the Brazilian Public Health System (SUS). Clinical data from patients with types 2 and 3 SMA followed at nine national reference centers (2020-2021) were analyzed. A total of 155 patients were included: 76 with type 2 and 79 with type 3 SMA. Disease duration was longer in type 3 patients. Time from symptom onset to genetic confirmation was also longer in this group. Functional impairment was observed in both subtypes. Type 2 patients had lower HFMSE scores overall, though higher scores were seen among those on disease-modifying therapies. In type 3, earlier symptom onset and longer disease duration were associated with worse motor outcomes. HFMSE scores varied with treatment use and disease duration. Findings reveal the clinical heterogeneity of SMA and emphasize the impact of diagnostic delays and disease duration on function. Early diagnosis and ongoing multidisciplinary care are crucial.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856020","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":"Molecular Basis and Clinical Spectrum of WNT10A-Related Oligodontia.","authors":"Perennes Elise, Benkirane-Jessel Nadia, Anton Nicolas, Vandamme Thierry, Clauss François, Conzatti Guillaume","doi":"10.1111/cge.70178","DOIUrl":"https://doi.org/10.1111/cge.70178","url":null,"abstract":"<p><p>WNT10A mutations, a major genetic determinant of dental agenesis and ectodermal dysplasia, exert profound effects on craniofacial development. Although classified as rare disorders, these mutations account for more than half of oligodontia cases, reflecting their critical role. The associated phenotypes span a broad clinical spectrum, ranging from isolated tooth agenesis to complex multisystem disorders, including hypodontia, enamel and root defects, palmoplantar keratoderma, alopecia, nail dystrophy, skin xerosis, hypohidrosis, eyelid cysts, and skin cancer, skeletal abnormalities and impaired bone homeostasis, underscoring their systemic impact. This review synthesizes current biological and clinical knowledge by linking phenotypes of WNT10A mutations to disruptions in Wnt/β-catenin signaling and its interactions with BMP, SMAD, RANK/RANKL/OPG, VEGF, and other regulatory pathways. Altered pathway activity affects key processes in tooth morphogenesis, osteogenesis, cellular proliferation, and tissue maintenance, offering mechanistic explanations for the heterogeneity and severity of patient presentations. A clearer understanding of these pathways is essential for improving diagnosis and management of WNT10A-associated oligodontia, particularly in treatment planning for growth-dependent interventions, regenerative strategies, and implant rehabilitation. Despite significant progress, critical gaps remain in defining the molecular basis of variable expressivity and genotype-phenotype relationships. Elucidating these mechanisms will be pivotal for advancing precision approaches in dental and craniofacial care.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834209","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":"The Molecular Diagnosis of Myopathies: Integrating Genomic, Proteomic, and Pathological Insights Toward Precision Medicine.","authors":"Ludmila Alem, Denise de Abreu Pereira, Katia Carneiro","doi":"10.1111/cge.70180","DOIUrl":"https://doi.org/10.1111/cge.70180","url":null,"abstract":"<p><p>Genetic myopathies encompass a heterogeneous spectrum of neuromuscular disorders whose diagnosis remains challenging despite major technological advances. Traditional methods such as clinical evaluation, creatine kinase measurement, electromyography, and muscle histopathology remain valuable tools for recognizing disease patterns and, when clinically indicated, for complementing and guiding molecular investigations. However, genetically complex or atypical cases still lack an appropriate approach for assertive diagnosis. Aiming to shed light on emerging integrative molecular approaches, this review will discuss the evolving diagnostic landscape of myopathies, highlighting the integration of next-generation molecular tools with conventional methodologies for assertive diagnosis. Long-read sequencing and optical genome mapping have markedly increased diagnostic yield by enabling comprehensive detection of structural variants and complex genomic rearrangements in different myopathies. Complementary proteomic and transcriptomic analyses provide functional insight into how genetic variants alter protein expression and cellular pathways, supporting biomarker discovery and therapeutic development. Together, these omics approaches bridge the gap between genetic alterations and their functional and clinical manifestations in myopathies. They improve the interpretation of variants of uncertain significance, facilitate the identification of biomarkers linked with disease severity or therapeutic response, and support the development of personalized therapeutic strategies, advancing precision medicine in neuromuscular disorders.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834273","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 Genetic Characteristics of Patients With Novel and Uncertain Significance Variants in CTLA4: A Mexican Cohort.","authors":"Gabriela López-Herrera, Patricia O'Farrill-Romanillos, Juan Carlos Rodriguez-Alba, Noemí Gómez-Hernández, Héctor Gómez-Tello Hector, Ana Eunice Fregoso-Zúñiga, Marco Antonio Yamazaki-Nakashimada, Francisco Javier Espinosa-Rosales, Daniela Pérez-Pérez","doi":"10.1111/cge.70179","DOIUrl":"https://doi.org/10.1111/cge.70179","url":null,"abstract":"<p><p>CTLA-4 haploinsufficiency is caused by heterozygous variants in CTLA4. We report a cohort of five patients with a clinical presentation including immune dysregulation, hypogammaglobulinemia, lung damage, and gastrointestinal symptoms, consistent with CTLA-4 haploinsufficiency. Patients ranged from 10 to 23 years of age, with three presenting before 7 years. Immunoglobulin levels and lymphocyte subpopulations were evaluated. All the patients evaluated showed low levels of CTLA-4 and lymphoproliferation in unstimulated conditions. Treatment before genetic diagnosis consisted mainly of intravenous immunoglobulin replacement and pharmacological immunosuppression. Heterozygous variants in CTLA4 were detected by exome sequencing. Immunological evaluation revealed reduced CTLA-4 expression and spontaneous lymphoproliferation. The identified heterozygous CTLA4 variants included two novel variants, one previously classified as likely pathogenic, one as pathogenic, and one as a variant of uncertain significance. These findings expand the spectrum of CTLA4 variants and support their clinical relevance.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834156","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":"Discovery of PHB1 as a Novel Candidate Gene in Dominant Optic Atrophy.","authors":"Marija Volk, Aleš Maver, Martina Jarc Vidmar, Nuša Trošt, Tanja Višnjar, Ana Fakin, Lea Kovač, Maja Šuštar Habjan, Lucija Malinar, Sanja Petrović Pajić, Urška Dragin Jerman, Rok Romih, Marko Hawlina, Borut Peterlin","doi":"10.1111/cge.70174","DOIUrl":"https://doi.org/10.1111/cge.70174","url":null,"abstract":"<p><p>Hereditary optic neuropathies comprise a genetically heterogeneous group of disorders caused by pathogenic variants in mitochondrial and nuclear genes. Despite increasing diagnostic yields, many patients remain without a molecular diagnosis. We report a novel candidate heterozygous variant in the PHB1 (Prohibitin 1) gene in a large family affected by autosomal dominant optic atrophy. A three-generation family with slowly progressive visual acuity loss due to optic neuropathy and an apparent autosomal dominant pattern was clinically characterized and recruited for genetic counseling. Exome sequencing and genome-based linkage mapping were performed, alongside protein modeling and in vitro experiments to obtain functional evidence. Family-based whole-genome linkage mapping identified a heterozygous missense variant, c.440C>T (p.Ser147Phe), in PHB1 in all five affected individuals. The variant substitutes p.Ser147Phe within an evolutionarily conserved alpha-helix domain of PHB1, a mitochondrial protein with multiple roles. In silico modeling suggested that p.Ser147Phe may disrupt PHB1 stability and function through loss of hydrogen bonding, steric hindrance, and altered hydrophobic interactions. In vitro experiments suggested potential alterations in mitochondrial dynamics in variant carriers, including a changed ratio of L-OPA1 to S-OPA1 compared with non-carriers. We present initial evidence that PHB1 is a novel candidate gene potentially associated with dominant optic atrophy or a related mitochondrial disorder. This represents the first report implicating PHB1 in a Mendelian disease. Further studies are required to validate this association.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812005","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 POPDC2 Pathogenic Variant in a Young Patient With Cardiac Conduction Disease and Hypertrophic Cardiomyopathy.","authors":"Maria Pia Ciccone, Filippo Maria Panfili, Francesca Bacigalupo, Francesca Brusco, Lara Florean, Federica Re, Irene Bottillo","doi":"10.1111/cge.70131","DOIUrl":"10.1111/cge.70131","url":null,"abstract":"<p><p>We chronicle the diagnostic journey of a young patient suffering from severe arrhythmias and left ventricular hypertrophy, for which, after about 15 years of inconclusive genetic testing, a definitive diagnosis was made possible by finding an undescribed homozygous variant in POPDC2, a gene recently associated with CCDs and HCM.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"986-988"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849111","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":"Novel NUP210L Variants Cause Fertilization Failure and Male Infertility in Humans.","authors":"Keyu Ren, Gan Shen, Han Ma, Yantong Zheng, Yingteng Zhang, Chuan Jiang, Yihong Yang, Xiang Wang, Ying Shen","doi":"10.1111/cge.70175","DOIUrl":"https://doi.org/10.1111/cge.70175","url":null,"abstract":"<p><p>Fertilization failure remains a major cause of infertility and poor outcomes in assisted reproductive technology, yet the underlying genetic mechanisms are incompletely understood. In this study, we investigated two unrelated infertile men presenting with macrozoospermia and recurrent fertilization failure following intracytoplasmic sperm injection (ICSI). Whole-exome sequencing identified biallelic variants in NUP210L, including a homozygous variant (c.3361C>T) in one patient and compound heterozygous variants (c.3853C>G and c.2965G>T) in another, which were confirmed by Sanger sequencing and predicted to be deleterious. Functional analyses revealed markedly reduced NUP210L expression in the patients' spermatozoa. Morphological assessment by Papanicolaou staining and scanning electron microscopy showed enlarged and irregular sperm heads accompanied by multiple flagella, while severely impaired chromatin condensation was observed under transmission electron microscopy. Consistently, immunofluorescence demonstrated significantly decreased expression of the protamines PRM1 and PRM2, indicating disruption of the histone-to-protamine transition during spermatogenesis. Expression analyses further revealed that NUP210L is predominantly expressed in spermatids in both human and mouse testes, supporting its role in late spermatogenic stages. Collectively, these findings provide evidence linking NUP210L deficiency to impaired chromatin condensation and fertilization failure, thereby expanding the genetic spectrum of fertilization failure and offering crucial insights for genetic diagnosis and clinical management in assisted reproduction.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764618","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":"Unmasking Compound Heterozygosity in GYG1 Myopathy: Diagnostic Insights From RNA-Seq and Long-Read Genomics.","authors":"Deepak Panwar, Joseph D Farris, Danielle Schmidt, Emily J Blake, Jia W Tan, Elie Naddaf, Joshua Sonnen, Filippo Pinto E Vairo, Laura J Lambert, Klaas J Wierenga, Karthik Muthusamy, Eric W Klee","doi":"10.1111/cge.70173","DOIUrl":"https://doi.org/10.1111/cge.70173","url":null,"abstract":"<p><p>Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1, which encodes glycogenin-1. It is characterized by progressive muscle weakness and PAS-positive, diastase-resistant polyglucosan inclusions on muscle biopsy. We report a 64-year-old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice-site variant, NM_004130.4(GYG1):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4(GYG1):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA-seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long-range PCR results were inconclusive. Long-read GS definitively demonstrated that the two variants were in trans, establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult-onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA-seq, and long-read GS for resolving complex phasing challenges.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764616","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":"Identification of 19 Pathogenic Variants in a Clinically Heterogeneous Cohort With Suspected Inborn Errors of Metabolism.","authors":"Sumreena Mansoor, Sabeen Abid, Muhammad Imran, Munir Iqbal Malik, Qamar Ali, Shanawaz Hussain, Hafiz Asim Ali, Yasser Masood, Shehla Choudhry, Raheel Qamar, Maleeha Azam","doi":"10.1111/cge.70172","DOIUrl":"10.1111/cge.70172","url":null,"abstract":"<p><p>Inborn errors of metabolism (IEM) are frequently underdiagnosed in low-resource settings due to limited diagnostic infrastructure. We hypothesized that an integrated clinical-genomic approach could improve diagnosis and management of these conditions. Nineteen Pakistani families with clinically suspected IEM underwent systematic clinical assessment, available biochemical testing, and whole-exome sequencing (WES). Variants were classified according to ACMG/AMP guidelines using evidence from population databases, in silico prediction tools, segregation analysis, and genotype-phenotype correlation. Clinical diagnoses and management strategies were reassessed based on molecular findings. WES provided a molecular diagnosis in 90% (17/19) of families and enabled targeted therapeutic interventions in 70% (13/19). However, clinical outcomes were variable due to advanced disease in some cases and limited follow-up. Seven novel variants were identified in CYP27B1, DYM, MTTP, ALDH3A2, USP53, BRAF, and JAG1, while twelve recurrent mutations were detected in PIGN, GCDH, CLCN7, RNASEH2C, ABCB11, MPV17, IDUA, SMPD1, FBP1, SLC37A4, ACADM, and UGT1A1. Integrating genomic findings with clinical reassessment improved diagnostic precision. An integrated clinical-genomic approach enabled accurate diagnosis of pediatric IEM in resource-limited settings, with particular utility in children with metabolic disorders in a consanguineous population. Identification of both novel and recurrent variants expanded the genotypic and phenotypic spectrum of these disorders and highlighted the clinical utility of genomic diagnostics in optimizing patient care.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670938","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":"Functional Analysis and Clinical Data Reclassify the DICER1 c.4206+1G>C Variant, Leading to Exon 22 Skipping, as Likely Pathogenic","authors":"Sebastian Walpole,&nbsp;Miren Itxaso Santiago-Vela,&nbsp;Ulf Birkedal,&nbsp;Zhenyi Hong,&nbsp;Xavier Bofill-De Ros,&nbsp;Thomas van Overeem Hansen,&nbsp;Karin A. W. Wadt","doi":"10.1111/cge.70110","DOIUrl":"10.1111/cge.70110","url":null,"abstract":"<div>\u0000 \u0000 <p>Pathogenic germline variants in \u0000 <i>DICER1</i>\u0000 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli-Leydig cell tumour and a broader spectrum of pathologies. Here, we report a 35-year-old female with diagnoses of pineoblastoma, embryonal rhabdomyosarcoma, leiomyosarcoma, two meningiomas, and a germline \u0000 <i>DICER1</i>\u0000 c.4206+1G&gt;C, p.(?) variant. The variant was classified as a variant of unknown significance (VUS) based on the current ACMG/AMP gene-specific DICER1 guidelines. Additional functional analysis showed that the variant clearly abrogates the function of DICER1 and therefore PS3_Supporting evidence is included in the classification. Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG/AMP gene-specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence (PS3) code.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"109 5","pages":"931-936"},"PeriodicalIF":2.3,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585613","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}