Clinical Genetics最新文献

{"title":"Challenges and Pitfalls in Diagnosing Twins With Discordant BWS Phenotype","authors":"Iacopo Bellani,&nbsp;Valentina Trevisan,&nbsp;Germana Viscogliosi,&nbsp;Maria Grazia Pomponi,&nbsp;Pietro Chiurazzi,&nbsp;Alessandro Mussa,&nbsp;Giuseppe Zampino,&nbsp;Maurizio Genuardi,&nbsp;Chiara Leoni","doi":"10.1111/cge.70022","DOIUrl":"https://doi.org/10.1111/cge.70022","url":null,"abstract":"<p>Accurately diagnosing Beckwith–Wiedemann syndrome (BWS) in twins with discordant phenotypes is essential for personalized oncological monitoring and management. It is advisable to test both twins, even without phenotypic expression, and incorporate prenatal factors like assisted reproduction technologies and twin pregnancies into the diagnostic BWS scoring system.\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 5","pages":"609-611"},"PeriodicalIF":2.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145230610","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":"Humeroradial Synostosis: An Updated Classification and Differential Diagnosis Based on Genetic Aetiology","authors":"Fiona Leduc,&nbsp;Clémence Vanlerberghe,&nbsp;Fabienne Escande,&nbsp;Perrine Brunelle,&nbsp;Florence Petit,&nbsp;Anne Dieux","doi":"10.1111/cge.70023","DOIUrl":"10.1111/cge.70023","url":null,"abstract":"<p>Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or sporadic cases and observed either isolated or as part of a syndromic condition. According to an extensive review of the literature, a dozen known conditions may comprise an HRS. The present review aims to propose an updated classification based on molecular pathways (chondrogenesis and osteogenesis; limb development and patterning; genome regulation), combined with a concise overview of the conditions associated with HRS. This knowledge could guide molecular analyses, patient management and genetic counselling. As some cases remain unexplained, further genetic and epidemiological studies are required to evaluate the contribution of genetic and environmental factors in HRS physiopathology.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"379-392"},"PeriodicalIF":2.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Further Case Supporting PDCD6IP as the Gene Responsible for a Neurodevelopmental Disorder With Microcephaly","authors":"Alfonso Manuel D'Alessio,&nbsp;Annalaura Torella,&nbsp;Manuela Morleo,&nbsp;Vincenzo Nigro,&nbsp;TUDP Study Group,&nbsp;Nicola Brunetti-Pierri","doi":"10.1111/cge.70025","DOIUrl":"https://doi.org/10.1111/cge.70025","url":null,"abstract":"<p>Summary of clinical and molecular findings in patients with biallelic variants in <i>PDCD6IP</i>.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"488-490"},"PeriodicalIF":2.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929641","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 Basis of Hypsarrhythmia: Expanding the PHACTR1 Spectrum and Pathway to Targeted Therapy","authors":"Karen Willième,&nbsp;Annelies Dheedene,&nbsp;Arnaud Vanlander,&nbsp;Patrick Verloo,&nbsp;Helene Verhelst","doi":"10.1111/cge.70024","DOIUrl":"https://doi.org/10.1111/cge.70024","url":null,"abstract":"<p>We report a 5-month-old girl with a novel <i>PHACTR1</i> variant, presenting with infantile spasms and hypsarrhythmia. <i>PHACTR1</i> encodes a protein with a unique actin- and phosphatase-binding structure, interacting with Slack (<i>KCNT1</i>-encoded), a Na⁺-activated K⁺-channel linked to epilepsy. This shared pathway may offer a promising avenue to future therapy.\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 5","pages":"612-614"},"PeriodicalIF":2.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145230567","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 and Clinical Landscape of Osteogenesis Imperfecta: Unraveling Autosomal Recessive Forms, Therapeutic Outcomes, and Bone Mineral Density in Carriers.","authors":"Haseena Sait, Naik Adarsha, Amita Moirangthem, Deepti Saxena, Lokesh Sharma, Preeti Dabadgao, Avantika Gupta, Shubha R Phadke","doi":"10.1111/cge.70003","DOIUrl":"https://doi.org/10.1111/cge.70003","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosomal recessive (AR) forms, therapeutic outcomes, and bone mineral density (BMD) in carriers of AR OI-associated gene variants from the Indian population. A total of 78 clinically suspected OI patients were analyzed, yielding a high diagnostic rate of 92.3%. Exome sequencing was performed in all cases, with whole-genome sequencing in selected exome-negative cases. Autosomal dominant (AD) and AR OI accounted for 66% and 34% of cases, respectively. P3H1 (n = 11) was the most frequently implicated AR gene causing OI, followed by SERPINF1 (n = 5) and WNT1 (n = 4), with 79% of AR variants being novel. Phenotypic evaluation (n = 67) revealed fractures, short stature (87%), and bony deformities (84%) as predominant features. A rare homozygous COL1A1 variant was identified in one patient, while another patient harbored additional variants in AD OI genes, suggesting a potential digenic or modifier effect. Phenotypic severity followed the order from most to least severe: AR genes > COL1A2 (substitution and non-substitution) > COL1A1 (substitution > non-substitution). A self-designed, preliminary clinical severity scoring system ranked CRTAP followed by P3H1, as the AR genes associated with the most severe phenotypes. Therapeutic assessment showed a significant reduction in fracture incidence following zoledronate therapy only in the COL1A1 group, with no notable improvements in the COL1A2 or AR groups. Additionally, BMD evaluation in carrier parents of AR gene causing OI indicated a higher predisposition to low BMD among WNT1 gene carriers. However, these findings are preliminary and limited by small sample size. This study provides an extensive genotypic and phenotypic characterization of OI in the Indian population, with a focus on AR OI. It documents differential therapeutic responses among genetic subgroups and provides preliminary observations on BMD in carrier parents of AR OI-an aspect that has been less explored previously and suggest the need for tailored management strategies. The findings in this study also raise the possibility of genetic modifiers contributing to phenotypic variability, warranting further investigation.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616610","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":"Ictal Asystole in a Patient With DEE due to an FGF12 Pathogenic Variant: A Reminder to Monitor Cardiac Function","authors":"Johanne Piotrowski,&nbsp;Élise Schaefer,&nbsp;Michael Kuntz,&nbsp;Virginie Bois,&nbsp;Franz Schieffer,&nbsp;Laurence Jesel,&nbsp;Margaux Biehler,&nbsp;Anne De Saint Martin,&nbsp;Sarah Baer","doi":"10.1111/cge.70018","DOIUrl":"https://doi.org/10.1111/cge.70018","url":null,"abstract":"<p>We report the first known case of a 9-year-old male with early-onset epilepsy, syncope, and ictal asystole–requiring pacemaker implantation at the age of seven–associated with a pathogenic variant in <i>FGF12</i>.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"486-487"},"PeriodicalIF":2.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929990","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":"SLC25A42-Related Mitochondrial Disorder: New Cases and Literature Review.","authors":"Areej Alatawi, Omamah Alshehri, Aminah Alessa, Fuad Al Mutairi, Norah AlSaleh, Wafaa Eyaid, Ali Alsamri, Eissa Faqeih, Aziza Mushiba, Mohammed Saleh, Maha Alotaibi, Brahim Tabarki, Yaser I Aljadhai, Panagiotis Katsonis, Olivier Lichtarge, Fowzan S Alkuraya, Majid Alfadhel, Mohammed Almannai","doi":"10.1111/cge.70021","DOIUrl":"https://doi.org/10.1111/cge.70021","url":null,"abstract":"<p><p>SLC25A42 encodes a mitochondrial carrier that is responsible for the import of CoA into mitochondria. Biallelic pathogenic variants in SLC25A42 have been associated with a recently described mitochondrial disorder characterized by encephalomyopathy with variable severity. To date, 24 affected individuals from 16 different families have been reported. Most are of Arab descent who harbor the founder variant in SLC25A42 (c.871A>G, p.Asn291Asp). In this report, we present 23 additional individuals from 19 unrelated families and their clinical, radiological, and molecular findings. We show again that SLC25A42-related mitochondrial disorder is associated with extremely variable severity. Some individuals with mild presentation may be unrecognized, while others are prone to metabolic decompensations with neuro-regression and irreversible neurological insult, making early diagnosis important.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590524","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":"An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy.","authors":"S Rehan Ahmad, Md Zeyaullah, Abdullah M AlShahrani, Danish Qavi, Abdelrhman A G Altijani, Mohammad Suhail Khan, Khursheed Muzammil","doi":"10.1111/cge.70019","DOIUrl":"https://doi.org/10.1111/cge.70019","url":null,"abstract":"<p><p>Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously uncharacterized homozygous and autosomal recessive missense variant, c.1372G>C (p.Gly433Ala), in the autophagy gene ATG2A, identified in a 3-year-old female proband presenting with developmental regression, seizures, cerebellar ataxia, and MRI-confirmed diffuse cerebral and cerebellar atrophy. The affected residue, Gly433, is evolutionarily conserved across eukaryotes and predicted to be structurally and functionally critical. Computational modeling and molecular dynamics simulations revealed that the G433A substitution induces local β-sheet extension, increased protein flexibility, higher aggregation propensity, and global structural destabilization. Proband-derived fibroblasts expressing ATG2A-G433A showed normal transcript and protein levels, but exhibited mislocalization of ATG2A to the cytosol, reduced colocalization with LC3B, loss of autophagosome formation, and a marked increase in protein aggregates. Proteotoxic stress was further evidenced by significant accumulation of Proteostat- and SQSTM1-positive granules. Additionally, transcript levels of unfolded protein response markers (GRP78, PERK, ATF4, and CHOP) were significantly upregulated, suggesting increased ER stress signaling. Cell cycle analysis revealed a substantial increase in cell death in proband fibroblasts. Overall, our findings identify ATG2A as a potentially novel disease gene and its G433A variant as a pathogenic substitution that disrupts autophagy and proteostasis, driving neurodegeneration via aggregation-prone misfolding and autophagy failure. This work depicts the first clinical spectrum of ATG2A-related neurodegenerative disorders and highlights the importance of autophagy maintenance in pediatric neurodevelopmental processes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590523","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":"Biallelic Variants in TMEM17 Cause Meckel-Gruber Syndrome Within the Ciliopathy Spectrum","authors":"Luba M. Pardo,&nbsp;Javier Martini,&nbsp;Emir Zonic,&nbsp;Ligia S. Almeida,&nbsp;Maria Iqbal,&nbsp;Mukunth Sadagopan,&nbsp;Alejandra P. Reyes,&nbsp;Nayla Y. León,&nbsp;Mohthash Musambil,&nbsp;Majid Alfadhel,&nbsp;Farhan Javed Dar,&nbsp;Fadwah Tahir,&nbsp;Eman AlSulmi,&nbsp;Nourah Al Qahtani,&nbsp;Hatoon Ahmed Al Taifi,&nbsp;Mohammad Al Hamad,&nbsp;Bader Alhaddad,&nbsp;Sondos Almubayedh,&nbsp;Lama Alabdi,&nbsp;Fowzan S. Alkuraya,&nbsp;Brahim Tabarki,&nbsp;Amal Tawhari,&nbsp;Amal Alhashem,&nbsp;Peter Bauer,&nbsp;Aida Bertoli-Avella","doi":"10.1111/cge.14767","DOIUrl":"https://doi.org/10.1111/cge.14767","url":null,"abstract":"<div>\u0000 \u0000 <p>\u0000 <i>TMEM17</i> encodes a transition zone protein essential for ciliary function. Three cases with homozygous variants in <i>TMEM17</i> in primary ciliopathies (Joubert and Oral-Facial-Digital syndrome) have been reported. We investigated whether biallelic <i>TMEM17</i> variants contribute to primary ciliopathies. We queried our Biodatabank and evaluated the gene-disease relationship (GDR) according to the ClinGen recommendations. Four unrelated patients (four families) were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) and novel homozygous variants: NM_198276.3:c.4del p.(Glu2Serfs*58); NM_198276.3:c.366dup p.(Pro123Thrfs*9); and NM_198276.3:c.368C&gt;G p.(Pro123Arg). A fifth family lost three foetuses with MGS phenotype, both parents are heterozygote carriers (NM_198276.3:c.4del p.(Glu2Serfs*58)) but biological material from the foetuses was not available. The cases in this study had a severe prenatal phenotype, including encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality. This study strengthens the gene-disease association of <i>TMEM17</i>, upgrading it from “limited” to “moderate.” We expand the phenotypic spectrum, ranging from MGS—with prenatal onset and early lethality—to Oral-Facial-Digital and Joubert syndromes. Our findings indicate that loss-of-function variants may underlie the most severe <i>TMEM17</i> ciliopathy manifestations, suggesting a potential genotype–phenotype correlation.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 5","pages":"582-588"},"PeriodicalIF":2.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145230636","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":"Prenatal Cell-Free DNA Screening With Fetal Enrichment Enables Sampling From 8 Weeks of Gestational Age.","authors":"Seyedeh Saideh Daryabari, Sylvie Giroux, André Caron, Jean-Claude Forest, Sylvie Langlois, Emmanuel Bujold, François Rousseau","doi":"10.1111/cge.70020","DOIUrl":"https://doi.org/10.1111/cge.70020","url":null,"abstract":"<p><p>Cell-free DNA (cfDNA) screening for fetal aneuploidy is typically offered from 10 weeks of gestational age (GA) onward. Fetal fraction (FF) enrichment may enable screening before 10 weeks with a low failure rate. This study aimed to assess the feasibility of cfDNA screening with in vitro enrichment before 10 weeks of gestation. 435 pregnant women were recruited between 7w0d and 9w6d of GA (EARLY samples) and scheduled for a second cfDNA sample after 11 weeks of GA (12w+ samples). 371 women provided both an EARLY and a 12w+ sample, and we compared cfDNA results between EARLY and 12w+ samples and sex at birth. For sex determination using cfDNA, EARLY, and 12w+ samples were 100% concordant with clinical sex at birth. In 170 male pregnancies, EARLY samples 5.9% had FF < 4% after enrichment. Seven aneuploidies were observed early, but eight at 12+ weeks (one false positive after invasive diagnostic testing). We observed 4.4% spontaneous abortions between the EARLY and 12w+ sampling. Our findings suggest that in vitro fetal enrichment provides sufficient cfDNA for reliable prenatal cfDNA screening results as early as 8 weeks, but one limitation lies in the high proportion of spontaneous abortions before 12w0d.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567196","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}