Journal of Medical Genetics最新文献

{"title":"Genetic features and pharmacological rescue of novel Kv7.2 variants in patients with epilepsy.","authors":"Yue Song, Yang Xia, Ziyue Peng, Yuhuan Meng, Wenwen Jing, Li Xie, Tianhua Cao, Jiahui Zhang, Huilin Song, Lingdi Meng, Yi Zhang, Shengbin Sui, Di Mao, Ying Jia, Shupei Qiao, Shihui Yu, Xue Zhang","doi":"10.1136/jmg-2024-110141","DOIUrl":"10.1136/jmg-2024-110141","url":null,"abstract":"<p><strong>Background: </strong>Increasing evidence indicates a robust correlation between epilepsy and variants of the Kv7.2 (<i>KCNQ2</i>) channel, which is critically involved in directing M-currents and regulating neuronal excitability within the nervous system. With the advancement of next-generation sequencing, the identification of <i>KCNQ2</i> variants has surged. Nonetheless, their functional impacts are still being determined, introducing uncertainty into the diagnostic process for affected families and potentially hindering their ability to participate in targeted precision medicine trials. This study aims to elucidate the pathogenicity of these novel variants and explore potential therapeutic interventions.</p><p><strong>Methods: </strong>Whole-cell patch-clamp recordings, western blotting, and immunofluorescent staining were performed to elucidate the functional consequences of the identified variants. Moreover, coimmunoprecipitation techniques were conducted to explore protein interactions, thus facilitating a deeper understanding of the underlying pathogenetic mechanisms contributing to the disease. Ultimately, the effects of pharmacological interventions were evaluated in vitro using the patch-clamp technique.</p><p><strong>Results: </strong>Herein, we identified 12 novel <i>KCNQ2</i> variants, further expanding the mutational spectrum of <i>KCNQ2</i>. Our investigation revealed that one gain-of-function variant (p.L102V (c.304C>G)) and three loss-of-function variants (p.H328Q (c.984C>G), p.A336V (c.1007C>T) and p.D563Efs*22 (c.1688_1689insACTT)) had different impacts on the binding of calmodulin and phosphati-dylinositol-4,5-bisphosphate, potentially altering their localisation and protein stability. Furthermore, the application of ML213, unlike Retigabine and ICA-069673, led to a significant increase in the current of p.H328Q.</p><p><strong>Conclusion: </strong>This study expanded the mutational spectrum of <i>KCNQ2</i> and analysed the genetic and functional consequences, as well as the pharmacological rescue, of four <i>de novo KCNQ2</i> variants. These findings offer valuable insights into the precise medicine of <i>KCNQ2</i>-related epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"231-241"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>FLNA</i> genomic rearrangements in a 391 French bilateral periventricular nodular heterotopia cohort: prevalence and phenotypic correlations.","authors":"Henri Margot, Natalia Hernandez Poblete, Chloé Angelini, Julie Desforges, Julie Bouron, Benoit Arveiler, Caroline Rooryck, Cyril Goizet, Patricia Fergelot","doi":"10.1136/jmg-2024-110336","DOIUrl":"10.1136/jmg-2024-110336","url":null,"abstract":"<p><strong>Background: </strong><i>FLNA</i> loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of <i>FLNA</i> gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.</p><p><strong>Methods: </strong>A retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).</p><p><strong>Results: </strong><i>FLNA</i> variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31-48, often accompanied by a duplication of the neighbouring <i>EMD</i> gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.</p><p><strong>Conclusion: </strong><i>FLNA</i> CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"227-230"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental knowledge, attitudes, satisfaction and decisional conflict regarding whole genome sequencing in the Genomic Medicine Service: a multisite survey study in England.","authors":"Ria Patel, Bettina Friedrich, Saskia C Sanderson, Holly Ellard, Celine Lewis","doi":"10.1136/jmg-2024-110458","DOIUrl":"10.1136/jmg-2024-110458","url":null,"abstract":"<p><strong>Background: </strong>Whole genome sequencing (WGS) for paediatric rare disease diagnosis is now available as a first-line test for certain clinical indications in the Genomic Medicine Service in England. The aim of this study was to assess decisional conflict regarding WGS at the time of consent as well as parental knowledge, attitudes and satisfaction.</p><p><strong>Methods: </strong>We conducted a multisite quantitative survey including validated measures. Surveys were sent out across seven National Health Service Trusts in England to parents of children offered WGS, within 4 weeks of their appointment.</p><p><strong>Results: </strong>374/1366 survey responses were included in the final dataset. Parents were highly satisfied with their WGS appointment (mean=24.47/28), had low decisional conflict (mean=20.09/100) and felt they had received enough information and support to make an informed decision (83.9%). Parents had positive attitudes towards WGS (mean=18.17/20), and those who had discussed WGS with a genetic counsellor or genomic associate had significantly more positive attitudes than those seen by genetic consultants (p<0.001). Most parents (84.3%) strongly agreed (27.2%) or agreed (67.1%) that they had a clear understanding of what a genomic test is. Parents whose child's condition was reported as more serious (p=0.0011) felt less conflicted about their decision.</p><p><strong>Conclusions: </strong>The parents in this study had low decisional conflict and most felt they had made an informed decision. Further research after parents receive WGS results to assess whether any, and if so who, regrets their decision, is important.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"289-297"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental delay, musculoskeletal disorders and dysmorphia associated with a novel pathogenic interstitial deletion of chromosome 10q21.1q21.3.","authors":"Dibyendu Dutta, Jennifer Black, Emily A Montoya, Thomas Andrew Burrow, Joseph Shieh, Bobbi McGivern, Michelle Raymond, Christina B Sheedy, Scott C Smith, Ria Garg","doi":"10.1136/jmg-2024-110367","DOIUrl":"10.1136/jmg-2024-110367","url":null,"abstract":"<p><strong>Background: </strong>Previous reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in chromosome 10q with global developmental delay, musculoskeletal abnormalities, and dysmorphic features has not been previously reported.</p><p><strong>Methods: </strong>Genetic testing using whole exome sequencing (WES) was performed on three patients with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Sequencing reads were aligned to the human genome build GRCh37/UCSC hg19 and analysed for both sequence and copy number variants.</p><p><strong>Results: </strong>WES identified similar interstitial deletions in the 10q21.1q21.3 locus in all three patients. The deleted region includes online Mendelian inheritance in man (OMIM)-annotated genes with clinical significance, such as <i>ANK3</i> (*600465), <i>JMJD1C</i> (*604503), <i>EGR2</i> (*129010), <i>BICC1</i> (*614295), <i>ZNF365</i> (*607818) and <i>TFAM</i> (*600438). Deletion of this region is considered pathogenic and is implicated in the aetiology of the clinical phenotypes observed in these patients.</p><p><strong>Conclusions: </strong>This is the first report associating interstitial deletions in the 10q21.1q21.3 locus with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Our findings highlight the clinical significance of this deleted region and suggest possible mechanisms underlying the observed pathological phenotypes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"268-275"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in <i>FGD1</i> and management recommendations.","authors":"Médéric Jeanne, Nathalie Ronce, Solène Remizé, Stéphanie Arpin, Geneviève Baujat, Sylvain Breton, Florence Petit, Clémence Vanlerberghe, Anne Coeslier-Dieux, Sylvie Manouvrier-Hanu, Catherine Vincent-Delorme, Philippe Khau Van Kien, Julien Van-Gils, Chloé Quélin, Laurent Pasquier, Sylvie Odent, Florence Demurger, Fanny Laffargue, Christine Francannet, Dominique Martin-Coignard, Alexandra Afenjar, Sandra Whalen, Alain Verloes, Yline Capri, Andrée Delahaye, Julie Plaisancié, Philippe Labrune, Anne Destree, Isabelle Maystadt, Viorca Ciorna Monferrato, Bertrand Isidor, Marie Vincent, Nolwen Jean Marçais, Sophie Nambot, Elise Schaefer, Salima El Chehadeh, James Lespinasse, Patrick Collignon, Tiffany Busa, Nicole Philip, Marjolaine Willems, Marc Planes, Olivier M Vanakker, Laetitia Lambert, Bruno Leheup, Michèle Mathieu-Dramard, Gilles Morin, Klaus Dieterich, Emmanuelle Ginglinger, Allan Bayat, Meena Balasubramanian, Benjamin Dauriat, Damien Haye, Jeanne Amiel, Marlène Rio, Valérie Cormier-Daire, Annick Toutain","doi":"10.1136/jmg-2022-108868","DOIUrl":"10.1136/jmg-2022-108868","url":null,"abstract":"<p><strong>Background: </strong>Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the <i>FGD1</i> gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.</p><p><strong>Methods: </strong>Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in <i>FGD1</i>, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.</p><p><strong>Results: </strong>This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.</p><p><strong>Conclusion: </strong>A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of <i>FGD1</i> variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"258-267"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and clinical analysis of <i>OPTN</i> in amyotrophic lateral sclerosis.","authors":"Yi Xiao, Yushan Tan, Chunyu Li, Qianqian Wei, Qirui Jiang, Shichan Wang, Tianmi Yang, Junyu Lin, Lingyu Zhang, Huifang Shang","doi":"10.1136/jmg-2024-109978","DOIUrl":"10.1136/jmg-2024-109978","url":null,"abstract":"<p><strong>Background: </strong>Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (<i>OPTN</i>) mutations, as reported in prior studies. The study aimed to elucidate the correlation between <i>OPTN</i> genotypes and phenotypes.</p><p><strong>Methods: </strong><i>OPTN</i> gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of <i>OPTN</i> mutations and explore the relationship between the genotype and phenotype of patients with ALS with <i>OPTN</i>.</p><p><strong>Results: </strong>A total of 33 unrelated patients with ALS with 24 rare <i>OPTN</i> variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of <i>OPTN</i> variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.</p><p><strong>Conclusion: </strong>Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying <i>OPTN</i> variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"242-248"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease burden by <i>ALPL</i> variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry.","authors":"Priya S Kishnani, Lothar Seefried, Kathryn M Dahir, Gabriel Á Martos-Moreno, Wolfgang Högler, Cheryl R Greenberg, Shona Fang, Anna Petryk, William R Mowrey, Agnès Linglart, Keiichi Ozono","doi":"10.1136/jmg-2024-110383","DOIUrl":"10.1136/jmg-2024-110383","url":null,"abstract":"<p><strong>Background: </strong>Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of <i>ALPL</i> variants resulting in low alkaline phosphatase activity. The objective of this analysis was to compare HPP disease burden between patients with non-life-threatening disease in the Global HPP Registry who have one <i>ALPL</i> variant versus two or more <i>ALPL</i> variants.</p><p><strong>Methods: </strong>Patients were included if they had one or more <i>ALPL</i> variants identified through genetic testing and first HPP manifestations after 6 months of age. Assessments included history of HPP manifestations, Brief Pain Inventory-Short Form (BPI-SF), Health Assessment Questionnaire-Disability Index (HAQ-DI), 6-Min Walk Test (6MWT), Paediatric Quality of Life Inventory (PedsQL) and 36-Item Short-Form Survey V.2 (SF-36v2).</p><p><strong>Results: </strong>Of 685 included patients, 568 (82.9%) had one <i>ALPL</i> variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more <i>ALPL</i> variants had higher proportions of skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological (22.2% vs 8.8%) manifestations at last assessment. BPI-SF, HAQ-DI, PedsQL and SF-36v2 scores were similar between groups. Distances walked on the 6MWT were similar between groups for children. Distance walked was lower among adults with two or more variants (293 m (n=8)) than adults with one variant (466 m (n=103)), although the former group was very small.</p><p><strong>Conclusion: </strong>HPP disease burden is high in patients with HPP, regardless of <i>ALPL</i> variant number. While prevalence of HPP-specific manifestations was higher in patients with two or more variants than those with one variant, patient-reported outcomes were similar between groups.</p><p><strong>Trial registration number: </strong>NCT02306720; EUPAS13514.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"249-257"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homozygous missense variant in <i>C2orf69</i> causes early-onset neurodegeneration, leukoencephalopathy and autoinflammation.","authors":"Rachel Youjin Oh, Michael Maier, Susan Blaser, Jessie Cameron, Cynthia Hawkins, Bruno Reversade, Grace Yoon","doi":"10.1136/jmg-2024-110419","DOIUrl":"10.1136/jmg-2024-110419","url":null,"abstract":"<p><p>Biallelic pathogenic variants in <i>C2orf69</i> cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in <i>C2orf69</i> have been reported to date.We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C>G, p.(Pro107Arg) variant of uncertain significance (VUS) in <i>C2orf69</i> Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid-Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in <i>C2orf69</i>, causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in <i>C2orf69</i> This expands the clinical and genetic spectrum of <i>C2orf69</i>-related disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"206-209"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: 'Commentary on Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank' by Møller <i>et al</i>.","authors":"Joaquín Castillo-Iturra, Ariadna Sánchez, Leticia Moreira, Maria Pellisé, Francesc Balaguer","doi":"10.1136/jmg-2024-110468","DOIUrl":"10.1136/jmg-2024-110468","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"151"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual dimorphism in <i>SMAD3</i> pathogenic variant-harbouring individuals.","authors":"Julie Richer, Joe Davis Velchev, Sharan Goobie, Christie A Boswell-Patterson, Ingrid M B H van de Laar, Judith M A Verhagen, Marja W Wessels, Jolien W Roos-Hesselink, Ilse Luyckx, Hussein Al-Amodi, Michael W A Chu, Anne-Marie Laberge, Bekim Sadikovic, Tugce Balci, Aline Verstraeten, Bart Loeys","doi":"10.1136/jmg-2024-110219","DOIUrl":"10.1136/jmg-2024-110219","url":null,"abstract":"<p><strong>Background: </strong>Individuals harbouring <i>SMAD3</i> pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in <i>SMAD3-</i>variant-harbouring patients.</p><p><strong>Methods: </strong>We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in <i>SMAD3</i>. We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 <i>SMAD3</i> patients reported in the literature between 2011 and 2023.</p><p><strong>Results: </strong>In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028).</p><p><strong>Conclusions: </strong>Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"199-205"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}