Clinical Genetics最新文献

{"title":"Compound-Heterozygous PLVAP Missense Variants Associated With Attenuated Protein-Losing Enteropathy (DIAR10).","authors":"Jana Zídková, Dagmar Procházková, Petra Konečná, Kamila Réblová, Tereza Kramářová, Johana Kopčilová, Magdaléna Soukup Vodičková, Romana Borská, Lenka Fajkusová","doi":"10.1111/cge.70258","DOIUrl":"https://doi.org/10.1111/cge.70258","url":null,"abstract":"<p><p>A three-year-old girl with attenuated protein-losing enteropathy carried compound-heterozygous missense PLVAP variants inherited from unaffected non-consanguineous parents. The case supports residual PLVAP function in missense-associated DIAR10 and expands its genetic and clinical spectrum.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126838","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 ACAN Missense Variant in the G1 Domain Causes Short Stature, Advanced Bone Age, and Osteochondritis Dissecans: A Case Report and Literature Review.","authors":"Cuilan Lin, Dongxue Pan, Xin Lai, Simao Fu","doi":"10.1111/cge.70241","DOIUrl":"https://doi.org/10.1111/cge.70241","url":null,"abstract":"<p><p>Heterozygous ACAN variants are a major monogenic cause of short stature (SS). We reported a 7 years and 11 months Chinese girl with SS, advanced bone age (BA), and asymptomatic knee osteochondritis dissecans. Targeted next generation sequencing identified a novel paternally inherited heterozygous ACAN missense variant c.547G>C within the G1 domain, classified as likely pathogenic per ACMG standards. Recombinant human growth hormone (rhGH) induced robust early catch up growth followed by reduced growth velocity, and the patient remains under follow up. This case expands the aggrecanopathy variant spectrum and supports routine ACAN screening in children with unexplained SS, accelerated BA, and osteochondral lesions.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104859","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":"Uncovering the Genetic Landscape of Pediatric Hearing Loss Along the Texas–Mexico Border","authors":"Desiree Lanehart,&nbsp;Michelle Gray,&nbsp;Roberta Sierra,&nbsp;Camille Maldonado,&nbsp;Daniel Brooks,&nbsp;Hongzheng Dai,&nbsp;Aaly Rahimtoola,&nbsp;Sandy Magallan,&nbsp;Sarah Rodriguez,&nbsp;Jose Gamez,&nbsp;Pattie Rosenlund,&nbsp;Surya N. Mulukutla,&nbsp;Alberto Allegre,&nbsp;Lori Berry,&nbsp;Brendan Lee,&nbsp;Daryl A. Scott,&nbsp;Blake Vuocolo,&nbsp;Seema R. Lalani","doi":"10.1111/cge.70224","DOIUrl":"10.1111/cge.70224","url":null,"abstract":"<p>Children in Health Professional Shortage Areas (HPSAs), including the US border regions, experience delays in the diagnosis of hereditary hearing loss (HL), driven primarily by limited access to specialized genetic services. Although approximately 60% of congenital HL has a genetic etiology, many affected children in these communities remain undiagnosed, delaying timely intervention. Project GIVE is an NIH-funded virtual genomics program that expands access to genome sequencing (GS) for children with undiagnosed multisystemic conditions along the Texas–Mexico border in the Rio Grande Valley (RGV) and El Paso regions of Texas, USA. Children (0–18 years) with suspected rare diseases were referred by regional healthcare professionals through a virtual portal, Consultagene, and underwent comprehensive virtual clinical genetics evaluation and trio GS. Among 23 Hispanic/Latino children evaluated for HL, 16 (~70%) received a molecular diagnosis. Of these, 56% had changes to medical management. Our findings demonstrate that high diagnostic yield for pediatric HL can be achieved in under-resourced populations when genomic testing barriers are addressed. As targeted therapies for hereditary HL emerge, broader implementation of comprehensive genetic testing in HPSAs is crucial to ensure timely medical interventions.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"627-636"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817779","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":"The First Case of Isolated Uterine Atony as the Only Symptom in an Individual With ACTG2-Associated Visceral Myopathy","authors":"Brady A. Slater,&nbsp;Emily Muth,&nbsp;Naomi J. L. Meeks","doi":"10.1111/cge.70234","DOIUrl":"10.1111/cge.70234","url":null,"abstract":"<p>This research letter expands the phenotypic spectrum of <i>ACTG2</i>-associated autosomal dominant visceral myopathy to include isolated uterine involvement based on a case of an individual harboring a known pathogenic <i>ACTG2</i> variant with uterine atony as her only symptom.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"637-638"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788992","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":"Hereditary Polyneuropathy Experience of a Tertiary Single-Center in Türkiye: Beyond the Tip of the Iceberg","authors":"Şahin Avcı,&nbsp;Serpil Eraslan,&nbsp;Gulshan Yunisova,&nbsp;Merve Kaysin,&nbsp;Ayşe Nur Özdağ Acarlı,&nbsp;Ayfer Arduç Akçay,&nbsp;Hülya Kayserili,&nbsp;Z. Piraye Oflazer","doi":"10.1111/cge.70226","DOIUrl":"10.1111/cge.70226","url":null,"abstract":"<div>\u0000 \u0000 <p>Hereditary polyneuropathies (HPPs), including Charcot–Marie–Tooth disease (CMT), represent a genetically and clinically heterogeneous group of disorders. Overlapping phenotypes, genetics, and clinical heterogeneity, and more complex phenotypes mimicking CMT can complicate the diagnosis. This study evaluated the effectiveness of an algorithm-guided, broad genetic testing strategy in a tertiary neuromuscular center in Türkiye, where recessive disorders are relatively common. Sixty-seven patients from 63 families referred for suspected HPP (2018–2025) were clinically stratified by phenotype and electrophysiology, and a diagnostic workflow integrating <i>PMP22</i> MLPA with clinical or whole-exome sequencing was applied. The overall molecular diagnostic yield was 73% (46/63). <i>PMP22</i>-related neuropathies accounted for 43.5% of all diagnosed cases, with a group-specific yield of 60%. Among the non-<i>PMP22</i> CMT group, the predominant inheritance pattern was autosomal recessive (70%). Nine novel variants were identified. Two dual molecular diagnoses (<i>PMP22</i>/<i>MCCC1</i>; <i>MPZ</i>/<i>CRYBB2</i>) were established. Importantly, six patients initially labeled as “CMT-like” harbored non-CMT disorders, including <i>CYP27A1</i>-, <i>BTD</i>-, <i>HEXB</i>-, <i>ZFYVE26</i>-, <i>C19ORF12</i>-, and <i>COA7</i>-related diseases—several of which are treatable or actionable. In a population with high genetic heterogeneity and elevated consanguinity, reliance on narrow CMT-focused panels risks misdiagnosis and may miss therapeutic opportunities. An algorithm-driven approach integrating <i>PMP22</i> CNV analysis with exome sequencing substantially improves diagnostic yield, reveals blended or digenic mechanisms, and helps distinguish non-CMT phenocopies. These findings underscore the importance of comprehensive genomic testing and careful phenotype–genotype correlation in the evaluation of hereditary polyneuropathies.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"549-557"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700947","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 De Novo DHX16 Variant Associated With Neuromuscular Oculoauditory Syndrome Regulates Pre-mRNA Splicing In Vitro","authors":"Yue Shen,&nbsp;Yunyu Zhou,&nbsp;Chao Lu,&nbsp;Zongfu Cao,&nbsp;Yufei Yu,&nbsp;Tingting Cheng,&nbsp;Huafang Gao,&nbsp;Minna Luo,&nbsp;Xu Ma,&nbsp;Ruifang Sui","doi":"10.1111/cge.70222","DOIUrl":"10.1111/cge.70222","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuromuscular oculoauditory syndrome (NMOAS; OMIM# 618733) is a rare neurodevelopmental disorder caused by heterozygous variants in <i>DHX16</i>, a gene in the DExD/H-box RNA helicase family. Despite increasing reports of DHX16-related NMOAS, the functional impact of specific variants on RNA splicing remains poorly understood. In this study, whole-exome sequencing identified a de novo DHX16 variant (c.1360C&gt;G, p.Arg454Gly) in a 2-year-old boy with NMOAS. In vitro assays revealed aberrant intron retention in HSPH1 and FOS transcripts in cells expressing the mutant DHX16-1360G, suggesting impaired splicing efficiency. Longitudinal clinical follow-up uncovered progressive multisystem involvement, including delayed gonadal development and autism spectrum disorder phenotypes not previously linked to DHX16. These findings expand the genotypic and phenotypic spectrum of NMOAS, confirm the pathogenic role of this variant in splicing dysregulation, and emphasize the need for long-term monitoring of emerging comorbidities in affected patients.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"598-604"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683790","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 De Novo ATP1A3 p.Arg995His Variant in a Patient With an Adult-Onset Primary Lateral Sclerosis-Like Syndrome.","authors":"Pablo Hernandez-Vitorique, Marta García de Burgos, Ana Campos Villegas, María José Gómez Heredia, Pilar Carbonell Corvillo","doi":"10.1111/cge.70254","DOIUrl":"https://doi.org/10.1111/cge.70254","url":null,"abstract":"<p><p>Pathogenic variants in ATP1A3 are classically associated with alternating hemiplegia of childhood, CAPOS syndrome, and rapid-onset dystonia-parkinsonism. However, the phenotypic spectrum of ATP1A3-related disease has expanded considerably in recent years, including atypical presentations with spasticity and hereditary spastic paraplegia-like phenotypes. We describe a 43-year-old woman who developed a progressive upper motor neuron syndrome characterized by spastic paraparesis, generalized hyperreflexia, bilateral Babinski signs, inexhaustible ankle clonus, spastic dysarthria, dysphagia, and mild cerebellar involvement. Extensive metabolic, autoimmune, infectious, neurophysiological, neuroimaging, and genetic investigations failed to identify an alternative diagnosis. Targeted next-generation sequencing identified a heterozygous ATP1A3 NM_152296.4:c.2984G>A, p.(Arg995His). Familial segregation analysis demonstrated a confirmed de novo occurrence with biological parentage verification. The variant affects a highly conserved residue within the transmembrane M8 domain, is absent from population databases, and is predicted to be deleterious by multiple in silico tools. According to ACMG/AMP criteria, the variant fulfilled PM2 and PP3 and is currently classified as a variant of uncertain significance (VUS). This case suggests a possible expansion of the phenotypic spectrum of ATP1A3-related disease and represents, to our knowledge, the first reported adult-onset primary lateral sclerosis-like phenotype associated with an ATP1A3 variant. These findings suggest that ATP1A3 should be considered in the genetic evaluation of unexplained adult-onset upper motor neuron syndromes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104883","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":"Two Novel ACTC1 Variants Cause Arthrogryposis Multiplex Congenita","authors":"Lauren Kerr,&nbsp;Pierre Moffatt,&nbsp;Lauren Hyer,&nbsp;Sarah Nossov,&nbsp;Noémi Dahan-Oliel,&nbsp;Frank Rauch","doi":"10.1111/cge.70218","DOIUrl":"10.1111/cge.70218","url":null,"abstract":"<p>Arthrogryposis multiplex congenita (AMC) is a group of conditions with congenital joint contractures in at least two body regions. <i>ACTC1</i> variants cause heart disorders but have also been reported in six families with AMC. We report on two individuals with AMC who were heterozygous for <i>ACTC1</i> missense variants (NM_005159.5; c.325G&gt;A, p.Glu109Lys and c.650A&gt;C, p.Lys217Thr). Individual 1 had scoliosis and no reported cardiac phenotype. Individual 2 had Shone's complex with coarctation of the aorta, which has not been reported in <i>ACTC1</i>-related AMC before. In vitro testing demonstrated that p.Glu109Lys caused impaired actin filament assembly and reduced ACTC1 protein levels, effects not apparent for p.Lys217Thr. Our findings characterize two novel variants that cause <i>ACTC1</i>-related AMC and expand the list of phenotypes observed in this disorder.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"584-589"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454829","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":"Surviving Males With PORCN Variants: Expanding the Clinical, Molecular, and Mechanistic Spectrum","authors":"Lucía Miranda-Alcaraz,&nbsp;Simone Carbonera,&nbsp;Mónica Mora-Gómez,&nbsp;Natalia Gallego-Zazo,&nbsp;Inmaculada Guillén,&nbsp;Elena Padilla,&nbsp;Gaia Visani,&nbsp;Alessia Asaro,&nbsp;Valeria Vásquez-Amell,&nbsp;Mario Cazalla,&nbsp;Manuel Rodríguez-Canó,&nbsp;Cristina Silván,&nbsp;Pedro Arias,&nbsp;Juan Andrés Jiménez-Estrada,&nbsp;Tomás Valle,&nbsp;Alejandro Cruz-Utrilla,&nbsp;Pilar Escribano-Subías,&nbsp;Nuria Ochoa Parra,&nbsp;María Jesús del Cerro Marín,&nbsp;Julián Nevado,&nbsp;Spanish PAH Consortium,&nbsp;Pablo Lapunzina,&nbsp;Fabio Sirchia,&nbsp;Jair Tenorio-Castano","doi":"10.1111/cge.70228","DOIUrl":"10.1111/cge.70228","url":null,"abstract":"<p>Pathogenic variants in <i>PORCN</i> cause focal dermal hypoplasia (FDH/Goltz syndrome), an X-linked dominant disorder historically considered lethal in males, with milder presentations now recognized as PORCN non-Goltz spectrum (PONGOS). We report three male patients identified by exome sequencing: one with a mosaic de novo variant (c.727C&gt;T; p.Arg243*) showing FDH features, and two siblings with an inherited non-mosaic variant (c.1315T&gt;G; p.Trp439Gly) from their unaffected carrier mother with a PONGOS phenotype. These cases confirm that male survival is possible with both mosaic and non-mosaic <i>PORCN</i> variants and expand the clinical and molecular spectrum of the disease. Our findings highlight the role of residual protein function in clinical variability and have important implications for diagnosis, genetic counseling, and management in families with apparently unaffected carrier mothers.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"605-615"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705676","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":"Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9, PKD1L1, MMP21, and GDF1","authors":"Thi Bich Tuyen Ho,&nbsp;Alicia Coudert,&nbsp;Thi Thuy Hang Do,&nbsp;Thi Thanh Thuy Le,&nbsp;Marjolaine Gauthier,&nbsp;Charlotte Dubucs,&nbsp;Jeremie Mortreux,&nbsp;Pauline Monin,&nbsp;Nicolas Chatron,&nbsp;Françoise Devillard,&nbsp;Charles Coutton,&nbsp;Véronique Satre,&nbsp;Radu Harbuz,&nbsp;William Dufour,&nbsp;Louis Januel,&nbsp;Tristan Celse,&nbsp;Clara Paris,&nbsp;Auragen Consortium,&nbsp;Le Tuyet Mai Tran,&nbsp;Huu Tung Trinh,&nbsp;Pierre-Simon Jouk,&nbsp;Ba Luu Truong,&nbsp;Thi Kim Nhi Nguyen,&nbsp;Julien Thevenon","doi":"10.1111/cge.70227","DOIUrl":"10.1111/cge.70227","url":null,"abstract":"<p>Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%–30% of HTX cases. To address this diagnostic gap, we collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam. In parallel, we conducted a systematic review of 108 published cases to refine genotype–phenotype correlations. We identified seven variants in four key genes: <i>DNAH9</i>, <i>PKD1L1</i>, <i>MMP21</i>, and <i>GDF1</i>. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype–phenotype correlations, such as the association of <i>MMP21</i> and <i>GDF1</i> variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"574-583"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788844","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}