Clinical Genetics最新文献

{"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}

{"title":"Spinal Muscular Atrophy in Adult Neurology Services in India","authors":"Farsana Mustafa,&nbsp;William L. Macken,&nbsp;Lindsay A. Wilson,&nbsp;Nimita Rani,&nbsp;Ayush Agarwal,&nbsp;Ajay Garg,&nbsp;Neerja Gupta,&nbsp;Rohit Bhatia,&nbsp;Roopa Rajan,&nbsp;Anu Gupta,&nbsp;Mamta Bhushan Singh,&nbsp;Vasantha Sarvade,&nbsp;Robert D. S. Pitceathly,&nbsp;Mary M. Reilly,&nbsp;Michael G. Hanna,&nbsp;Ashwin Dalal,&nbsp;Kumarasamy Thangaraj,&nbsp;Venugopalan Y. Vishnu","doi":"10.1111/cge.70221","DOIUrl":"10.1111/cge.70221","url":null,"abstract":"<div>\u0000 \u0000 <p>Spinal muscular atrophy (SMA) research has focused predominantly on paediatric populations, with limited adult data from low- and middle-income countries (LMICs). We prospectively recruited suspected SMA patients (age ≥ 12 years) into a neuromuscular disease cohort at a tertiary centre in northern India, using phenotyping, creatine kinase, electrophysiology and genetic testing. Forty genetically confirmed patients were included (median age 20.5 years; mean symptom duration 14.7 ± 10.9 years). Proximal lower-limb weakness was the commonest presentation (82.5%). Forty-five percent were misdiagnosed as muscular dystrophy or congenital myopathy. Three SMA patients received risdiplam. Our cohort highlights the diagnostic challenges of adult SMA and supports a genetics-first approach. Early genetic confirmation shortens diagnostic delay, reduces misclassification and helps eligible patients benefit as disease-modifying therapies become more affordable in resource-limited settings.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"590-597"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629832","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 Architecture of Pediatric Cardiomyopathies Assessed by Whole-Exome Sequencing: Insights Into Early-Onset and Syndromic Forms","authors":"Luana Giovannangeli,&nbsp;Elise Daire,&nbsp;Kahia Messaoudi,&nbsp;Didier Herent,&nbsp;Nathalie Desjeux,&nbsp;Emilie Lacot-Leriche,&nbsp;Sarah Sauval,&nbsp;Sabine Dirani,&nbsp;Pascal De Groote,&nbsp;Didier Klug,&nbsp;Jean-Benoit Baudelet,&nbsp;Alexandre Delarue,&nbsp;Olivia Domanski,&nbsp;Pierre-Alexandre Fontanges,&nbsp;Jamal Ghoumid,&nbsp;Luisa Marsili,&nbsp;Alexis Hermida,&nbsp;Florence Jobic,&nbsp;Guillaume Jedraszak","doi":"10.1111/cge.70230","DOIUrl":"10.1111/cge.70230","url":null,"abstract":"<p>Pediatric cardiomyopathies (CM) are rare and heterogeneous heart disorders, including hypertrophic, dilated, restrictive, arrhythmogenic, and non-dilated CM. While their genetic basis is well characterized in adults, it remains less clearly defined in children particularly in early-onset apparently isolated and syndromic forms. We conducted a retrospective study (2018–2024) of 59 pediatric patients who underwent Whole-Exome Sequencing (WES) for CM at Amiens and Lille University Hospitals, aiming to characterize the genetic architecture of pediatric CM. WES identified at least one Variant Of Interest (VOI) in 62.7% of patients (37/59), including 45.8% (27/59) of P/LP variants, and 16.9% (10/59) of VUS. VOI identification yields for HCM and DCM were respectively 67.7% and 57.1%. Yield was higher in patients diagnosed before 1 year of age compared with those diagnosed later (72.7% vs. 56.7%). Variants were identified in classical CM genes, including sarcomeric genes, but also in less typical and syndromic genes. Among patients diagnosed before 6 months, 55% carried a variant in genes associated with syndromic cardiomyopathy, including cases with initially isolated cardiac phenotypes. These findings support the use of WES as a first-line approach in pediatric CM and highlight the contribution of complex and syndromic genetic architectures to early-onset and severe diseases.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"622-626"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757786","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":"Biallelic Truncating Variant in LRGUK Is Associated With Severe Multiple Morphological Abnormalities of the Sperm Flagella and Sperm Nuclear Defects in Humans","authors":"Wiâme Mokkedem,&nbsp;Zeina Wehbe,&nbsp;Anne-Laure Barbotin,&nbsp;Angèle Boursier,&nbsp;Célia Tebbakh,&nbsp;Nicolas Thierry-Mieg,&nbsp;Marie Bidart,&nbsp;Antonella Migliaccio,&nbsp;Rosanna Chianese,&nbsp;Christophe Arnoult,&nbsp;Raoudha Zouari,&nbsp;Zine-Eddine Kherraf,&nbsp;Pierre F. Ray,&nbsp;Guillaume Martinez,&nbsp;Charles Coutton","doi":"10.1111/cge.70220","DOIUrl":"10.1111/cge.70220","url":null,"abstract":"<p>Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility characterized by immotile spermatozoa with absent, short, coiled, or irregular flagella. Despite advances in whole-exome sequencing, many cases remain genetically unexplained. Here, we identify a homozygous truncating variant in <i>LRGUK</i> (c.1063C&gt;T; p.Arg355Ter) in an infertile man presenting with a typical MMAF phenotype. The variant, identified by whole-exome sequencing in a cohort of 168 MMAF patients and confirmed by Sanger sequencing, is predicted to result in loss of the C-terminal guanylate kinase-like domain. Immunofluorescence showed absence of LRGUK protein in patient spermatozoa, supporting a loss-of-function effect. Semen analysis revealed impaired motility and complete teratozoospermia. Morphological and ultrastructural analyzes demonstrated severe defects affecting both sperm head and flagellum, including disorganized axonemal architecture and central pair abnormalities. Nuclear analyzes showed increased nuclear size, defective chromatin compaction, and elevated DNA fragmentation. Immunostaining further indicated alterations of central apparatus-associated proteins, supporting a role for LRGUK in C1b projection organization. These findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"538-548"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577242","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":"Establishing a Prognosis When Identifying Pathogenic Variants in Usher Syndrome/DFNB-Related Genes: An Impossible Challenge?","authors":"Ralyath Balogoun,&nbsp;Margaux Serey-Gaut,&nbsp;Laurence Jonard,&nbsp;Sandrine Marlin","doi":"10.1111/cge.70240","DOIUrl":"10.1111/cge.70240","url":null,"abstract":"<p>As our results show that very few published variants could currently be considered causative of DFNB due to lack of precise clinical studies, strict and uniform criteria should be applied by authors publishing on USH/DFNB genes.\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":"639-641"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838921","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":"Genetic Spectrum of Non-PTPN11 Variants in Noonan Syndrome and Related RASopathies: Findings From a Russian Cohort","authors":"Anna Orlova,&nbsp;Olga Shatokhina,&nbsp;Daria Guseva,&nbsp;Nina Demina,&nbsp;Aleksander Polyakov,&nbsp;Oхana Ryzkova","doi":"10.1111/cge.70211","DOIUrl":"10.1111/cge.70211","url":null,"abstract":"<p>Noonan syndrome (NS) and related RASopathies form a clinically and genetically heterogeneous group of disorders caused by germline dysregulation of the RAS/MAPK pathway. Pathogenic variants in PTPN11 account for roughly half of classical NS, but the contribution of non-PTPN11 genes in patients referred with NS or Noonan-like phenotypes remains incompletely defined in several populations, including Russia. We characterized the spectrum of non-PTPN11 variants in a large Russian cohort referred for suspected NS or Noonan-like phenotypes and examined gene-specific clinical patterns. We analyzed 456 unrelated patients with clinically diagnosed NS or Noonan-related syndromes using a targeted panel of 23 RAS/MAPK pathway genes. PTPN11 variants (23% of cases) were reported previously; here we focused on the remaining patients. Pathogenic or likely pathogenic variants were identified in 19% of cases (85/456), with NF1, SOS1, SHOC2, and BRAF being the most frequently mutated genes, together accounting for 50% of the non-PTPN11 diagnoses. Novel variants were observed in 12.1% of cases (7/58 unique variants). Several genotype–phenotype associations emerged: SOS1 mutations were associated with a high prevalence of cardiac defects, especially pulmonary stenosis and atrial septal defects (64% of patients, <i>p</i> = 0.01), whereas NF1 and SPRED1 cases had significantly fewer cardiac anomalies (<i>p</i> &lt; 0.001 and <i>p</i> &lt; 0.05, respectively). Lentigines were predominantly seen in NF1 and SPRED1 patients (<i>p</i> &lt; 0.01), and all three evaluable males with MAP2K1 variants had cryptorchidism (3/3). Conversely, BRAF-mutated patients showed lower incidence of chest deformity (<i>p</i> &lt; 0.01) but higher rates of developmental delay. NF1, SOS1, SHOC2, and BRAF together accounted for half of the non-PTPN11 molecular diagnoses in this Russian cohort, and the observed gene-specific clinical patterns align with previous series, although limited subgroup sizes preclude firm individual associations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"527-537"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374702","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":"Two Japanese Cases Highlighting Structural and Phenotypic Overlap in AGO1- and AGO2-Related Neurodevelopmental Disorders","authors":"Munetsugu Hara,&nbsp;Nobuhiko Okamoto,&nbsp;Yukihiro Kitai,&nbsp;Yoriko Watanabe,&nbsp;Naoko Matsumoto,&nbsp;Kaori Fukui,&nbsp;Ryuta Takase,&nbsp;Yukina Hayashi,&nbsp;Atsushi Fujita,&nbsp;Kumiko Yanagi,&nbsp;Tadashi Kaname,&nbsp;Naomichi Matsumoto","doi":"10.1111/cge.70229","DOIUrl":"10.1111/cge.70229","url":null,"abstract":"<div>\u0000 \u0000 <p>Pathogenic variants in AGO1 and AGO2, core components of the Argonaute family, have emerged as causes of rare neurodevelopmental disorders characterized by intellectual disability, marked language impairment, behavioral abnormalities, and distinctive craniofacial features. Reported variants cluster at the L1–PAZ boundary, a structurally sensitive region essential for guide-RNA engagement. We describe two unrelated Japanese individuals carrying de novo variants in <i>AGO1</i>(NM_012199.5):c.569T&gt;C p.(Leu190Pro) or <i>AGO2</i>(NM_012154.6):c.544_546del p.(Phe182del), affecting structurally corresponding residues within this boundary. Both individuals exhibited global developmental delay, hypotonia, midface hypoplasia, thin upper lip, elongated facial shape, and reduced cerebral white matter volume, aligning with previously reported AGO1- and AGO2-related phenotypes. Structural assessment using AlphaFold2-based AGO1 models and the AGO2 crystal structure confirmed positional equivalence of the affected residues, supporting the concept of a shared structural vulnerability across Argonaute paralogs. These observations expand the phenotypic spectrum of Argonaute-related neurodevelopmental disorders in the Japanese population and highlight RNA-regulatory dysfunction as a coherent pathogenic axis. Recognition of this clinical gestalt may assist clinicians in prioritizing AGO1 and AGO2 during genomic evaluation of unexplained neurodevelopmental disorders.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"616-621"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711523","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":"Sotos and Malan Syndromes in Childhood: Molecular and Clinical Findings From a Nationwide Cohort of 48 Patients","authors":"Ceren Yılmaz Uzman,&nbsp;Semra Gürsoy,&nbsp;Filiz Hazan,&nbsp;Durdugül Ayyıldız Emecen,&nbsp;Aslıhan Sanrı,&nbsp;Tahir Atik,&nbsp;Esra Işık,&nbsp;Türkan Turgut Tan,&nbsp;Yusufcan Doğan,&nbsp;Yasemin Alanay,&nbsp;Özlem Doğan Akgün,&nbsp;Nursel Elçioğlu,&nbsp;İrem Fikriye Akbolat Sakar,&nbsp;Suzan Süncak,&nbsp;Hatice Yelda Yalçın,&nbsp;Akçahan Akalın,&nbsp;Hayriye Nermin Keçeci,&nbsp;Nagehan Bilgeç,&nbsp;Hatice Mutlu,&nbsp;Arzu Ay,&nbsp;Özgür Balasar,&nbsp;Ebru Tunçez,&nbsp;Burcu Yeter,&nbsp;Yasemin Kendir Demirkol,&nbsp;Fayize Maden Bedel,&nbsp;Funda Kökali,&nbsp;Özlem Giray Bozkaya","doi":"10.1111/cge.70225","DOIUrl":"10.1111/cge.70225","url":null,"abstract":"<div>\u0000 \u0000 <p>Sotos syndrome is an overgrowth disorder caused by heterozygous <i>NSD1</i> variants, partial-gene deletions, or 5q35 microdeletions. Malan syndrome, a phenotypically overlapping condition, results from haploinsufficiency of the <i>NFIX</i> gene due to either heterozygous chromosomal microdeletions involving the 19p13.2 region or heterozygous loss-of-function variants. This multicenter study aimed to characterize the clinical and molecular features of individuals with Sotos and Malan syndromes in Türkiye. We retrospectively analyzed clinical and molecular data from 48 individuals with genetically confirmed Sotos or Malan syndrome across 14 centers. Molecular analyses included whole-exome sequencing, clinical exome sequencing, targeted gene panels, multiplex ligation–dependent probe amplification, and chromosomal microarray analysis. Forty-two individuals were diagnosed with Sotos syndrome and six with Malan syndrome. All exhibited characteristic facial features, and 97.9% had developmental delay or intellectual disability. We identified a total of 38 <i>NSD1</i> variants, of which 35 were classified as pathogenic or likely pathogenic and three as variants of uncertain significance; notably, 23 of these variants were novel. Three patients carried 5q35 microdeletions, and one had an intragenic deletion involving exons 10–11. Four distinct <i>NFIX</i> variants (two novel) were detected in five patients, and one carried a 19p13.13 deletion encompassing the entire gene. This nationwide study expands the genotype–phenotype spectrum of Sotos and Malan syndromes in Türkiye and supports improved diagnostic and clinical management strategies.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"110 5","pages":"558-573"},"PeriodicalIF":2.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789004","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 Homozygous Frameshift Variant in KHDC4 Is Associated With a Syndromic Inherited Retinal Disease in Humans.","authors":"Asodu Sandeep Sarma, Neta Barnoy, Prakadeeswari Gopalakrishnan, Keren Dichter, Rotem Mizrachi, Manar Salameh, Eyal Banin, Dror Sharon, Adi Inbal, Samer Khateb","doi":"10.1111/cge.70256","DOIUrl":"https://doi.org/10.1111/cge.70256","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) are genetically heterogeneous and often remain unsolved despite advanced sequencing. This study investigated two siblings from a consanguineous Arab-Christian family presenting with a syndromic IRD. Exome sequencing revealed a homozygous frameshift variant (c.1535_1538del:(p.Lys512Argfs*8) in the KHDC4 gene, which segregated with disease in an autosomal recessive pattern. In vitro overexpression of the mutant protein showed aberrant sub-cellular localization, and an in vivo zebrafish knockout model exhibited mild retinal dysfunction. These findings establish KHDC4 as a novel candidate gene for syndromic IRDs in humans, expanding the genetic landscape of the IRDs.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080005","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}