Journal of Medical Genetics最新文献

{"title":"Risk of breast cancer after ovarian cancer in germline <i>BRCA1/2</i> heterozygotes.","authors":"Robert D Morgan, Emma R Woodward, D Gareth Evans","doi":"10.1136/jmg-2026-111752","DOIUrl":"https://doi.org/10.1136/jmg-2026-111752","url":null,"abstract":"<p><p>Breast cancer risk after ovarian cancer in germline <i>BRCA1/2</i> heterozygotes remains uncertain, with a recent large multicentre international study reporting lower-than-expected incidence in the first decade after ovarian cancer diagnosis (Apostol et al. 2026). We re‑evaluated our previously published regional cohort of 701 women with ovarian cancer and a germline <i>BRCA1/2</i> pathogenic or likely pathogenic variant, restricting the analysis to those tested after ovarian cancer diagnosis and without prior breast cancer, to minimise ascertainment and survivor bias. In our refined cohort of 406 women, 19 breast cancers occurred over 1340.97 person‑years, giving an annual incidence of 1.42% (1.60% for <i>BRCA1</i> and 1.14% for <i>BRCA2</i>). Incidence was lowest within the first 5 years (0.88%/year) and increased beyond 10 years (1.89%/year). These estimates align closely with those reported recently by Apostol et al. Breast cancer incidence after ovarian cancer is low in the first decade but may rise thereafter. These findings support reassurance during early survivorship while recognising that long‑term survivors may still consider risk‑reducing mastectomy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818622","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":"Childhood-onset neurodegeneration and brain atrophy: defining <i>UBTF</i>-related developmental regression and progressive ataxia.","authors":"Amanda Nagy, Anna Luddy, Francine Molay, Haley McLaughlin, Lizbeth De La Rosa Abreu, Catherine Becker, Markus Terrey, Cathleen M Lutz, Anoopum Gupta, Florian S Eichler","doi":"10.1136/jmg-2025-111356","DOIUrl":"10.1136/jmg-2025-111356","url":null,"abstract":"<p><strong>Background: </strong>The heterozygous variant c.628G>A (p.Glu210Lys) in <i>UBTF</i> (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed development followed by regression, with individuals frequently experiencing movement disorders. This study defines the natural history of this rare disorder and explores potential biomarkers in humans and mice.</p><p><strong>Methods: </strong>Caregivers of individuals with CONDBA completed cross-sectional surveys detailing genetic, developmental and clinical features. Patients evaluated in a neurogenetics clinic underwent Brief Ataxia Rating Scale (BARS) assessments compared with remotely collected wrist and ankle accelerometry data. Neurofilament light chain (NFL) levels were assessed in the clinic cohort and in a Ubtf E210K knock-in mouse model.</p><p><strong>Results: </strong>All 11 caregiver surveys reported onset of neurodevelopmental regression (median 3.5 years, range 0.5-5 years), at times following anaesthesia or illness and 82% developed ataxia. Motor activity data from five participants (median 11.8 years, range 8.1-12.5 years) had high test-retest reliability, correlated with ataxia severity as measured by the BARS, and showed declines across multiple measures over the study period. NFL was abnormally elevated in both humans and the mouse model.</p><p><strong>Conclusion: </strong><i>UBTF</i>-related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia. Wearable accelerometers provide a reliable measure of disease severity, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760432","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":"<i>BHLHE22</i> monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities.","authors":"Carolyn Le, Tugba Kalayci, Zehra Uyguner, Birsen Karaman, Tanju Demirören, Bodo Beck, Nora Winnerling, Elizabeth George, Stephanie DiTroia, Delphine Héron, Isabelle Sabatier, Lance H Rodan, Katta M Girisha, Periyasamy Radhakrishnan, Carol Saunders, Bonnie Sullivan, Emily Fleming, Javeria Raza Alvi, Tipu Sultan, Henry Houlden, Stephanie Efthymiou, Maria J Guillen Sacoto, Melanie Goodman, Lucie Pierron, Jean-Madeleine de Sainte Agathe, Alexandra Durr, Hector Rodrigo Mendez, Matthew T Wheeler, Jennefer N Carter, Jonathan A Bernstein, Biljana Gagachovska, Slavica Trajkova, Alfredo Brusco, Elliott Sherr, Emanuela Argilli","doi":"10.1136/jmg-2025-111432","DOIUrl":"10.1136/jmg-2025-111432","url":null,"abstract":"<p><strong>Background: </strong><i>BHLHE22</i> encodes a basic helix-loop-helix transcription factor expressed exclusively in the retina and central nervous system and functions as an important regulator of neuronal differentiation. However, <i>BHLHE22</i> has not yet been associated with a Mendelian neurodevelopmental or neurological disorder.</p><p><strong>Methods: </strong>15 individuals from 13 unrelated families carrying <i>BHLHE22</i> variants identified by exome sequencing were collected through an international collaboration.</p><p><strong>Results: </strong><i>De novo</i> missense variants located in the highly conserved helix-loop-helix domain of the protein were found in six individuals, and one recurrent homozygous frameshift variant, NP_689627.1:p.Gly74AlafsTer18, was found in nine individuals. Frequent clinical features include absent or limited speech (10/13), delayed or impaired motor abilities (11/13), intellectual disability (ID; 9/12), partial or complete agenesis of the corpus callosum (12/15), involuntary movements and/or stereotypies (11/13) and abnormal muscle tone (13/13), depending on data availability. Two individuals developed spastic paraplegia, without ID or callosal anomalies. One individual had moderate developmental delay and ID but without callosal anomalies.</p><p><strong>Conclusion: </strong>Collectively, our data establish <i>BHLHE22</i> as a previously unrecognized neurodevelopmental disease gene. Disruption of <i>BHLHE22</i>, through either dominant or recessive variants, results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726876","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":"Evolving roles within the genomic medicine workforce: a revised framework for UK practice-position on behalf of the Association of Genetic Nurses and Counsellors and the Clinical Genetics Society.","authors":"Roberta Rizzo, Meena Balasubramanian, Diana Baralle, Catriona Corsie, Catherine Houghton, Bethany Lumborg, Emma Tonkin, Mohnish Suri","doi":"10.1136/jmg-2025-111340","DOIUrl":"10.1136/jmg-2025-111340","url":null,"abstract":"<p><p>This document is written on behalf of the two professional bodies in the UK that represent genetic counsellors (the Association of Genetic Nurses and Counsellors (AGNC)) and clinical geneticists (the Clinical Genetics Society). The delivery of genomic medicine in the UK continues to evolve in response to technological advancements, increasing demand and national strategic priorities. This paper presents an updated framework describing the professional roles within specialist genomic services, refining responsibilities across key domains of clinical care, education, research and mainstreaming.Building on previous role descriptors, through focused workshops with specific expertise, we integrated national consultation, emerging service models and policy alignment. A new colour-coded matrix delineates role-specific scope of practice for different roles as described in the AGNC career structure.A key development is the formal inclusion of the genomic practitioner role, reflecting workforce diversification. Expanded emphasis is placed on mainstreaming genomic services and involvement in clinical and psychosocial research.This updated framework provides a structured and transparent tool for workforce planning, interprofessional collaboration and service development across genomic medicine. The framework remains aspirational and adaptable, acknowledging regional variability and anticipating future service developments.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723453","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":"Actionable genotypes beyond the coding sequence and their association with lifespan in the UK Biobank.","authors":"Congcong Chen, Jiawen Zhu, Ziye Xu, Xinyu Gu, Yanan Shi, Yingjia Chen, Yuan Xie, Xin Yuan, Qiqi Zhai, Jun Zhou, Na Qin, Juncheng Dai, Hongxia Ma, Guangfu Jin, Hongbing Shen, Zhibin Hu, Cheng Wang","doi":"10.1136/jmg-2026-111659","DOIUrl":"10.1136/jmg-2026-111659","url":null,"abstract":"<p><strong>Background: </strong>The identification and reporting of actionable genotypes in the American College of Medical Genetics and Genomics (ACMG)-recommended secondary findings (SF) genes represent a key preventive strategy for hereditary diseases. Robust evidence quantifying their association with lifespan remains limited, particularly for non-coding regulatory variants, due to functional interpretation challenges.</p><p><strong>Method: </strong>Using data from the UK Biobank, we investigated associations between genetic variants and all-cause mortality in 490 086 participants with whole-genome sequencing. We systematically interpreted pathogenic or likely pathogenic coding variants in the 81 genes listed in the ACMG SF V.3.2. In parallel, we conducted saturation mutagenesis combined with a massively parallel reporter assay on the core promoters of these genes to generate a functional map of every potential variant, which we then used to interpret the functionally promoter variants in the cohort and evaluated their associations with mortality and disease incidence.</p><p><strong>Results: </strong>Coding actionable genotypes were present in 3.40% of participants and were associated with increased all-cause mortality (HR in females, 1.42; 95% CI 1.34 to 1.52; HR in males, 1.31; 95% CI 1.24 to 1.39). All rare variants within the core promoter regions of these genes revealed no significant association with survival. Functionally promoter variants with downregulating activity of cancer genes were associated with elevated mortality risk (HR in females, 1.15; 95% CI 1.01 to 1.31; HR in males, 1.12; 95% CI 1.00 to 1.26). Furthermore, our findings provide clues that functional promoter variants may merit consideration when expanding actionable genotype lists.</p><p><strong>Conclusions: </strong>Our findings demonstrate that functionally verified promoter variants represent a previously unrecognised determinant of mortality risk, highlighting the potential value of looking beyond coding sequences in future studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721292","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":"Integrated D4Z4 structural, epigenetic and exome-based evaluation of facioscapulohumeral muscular dystrophy in a tertiary referral cohort from Türkiye.","authors":"Şahin Avcı, Serpil Eraslan, İlker Eren, Manar Kaptan, Beyza Yavuzcan, Ayse Nur Ozdag Acarli, Merve Celik Kaysin, Gulshan Yunisova, Ayfer Arduç Akçay, Mehmet Demirhan, Zehra Piraye Oflazer, Hülya Kayserili","doi":"10.1136/jmg-2026-111660","DOIUrl":"10.1136/jmg-2026-111660","url":null,"abstract":"<p><strong>Background: </strong>Diagnosing facioscapulohumeral muscular dystrophy (FSHD) requires integrated evaluation of D4Z4 repeat size, permissive haplotype status, epigenetic context and alternative molecular aetiologies, particularly in borderline, non-contracted or structurally complex cases.</p><p><strong>Methods: </strong>We evaluated 135 unrelated referrals with suspected FSHD at a tertiary referral centre in Türkiye between 2019 and 2026. First-line testing included single-molecule D4Z4 repeat sizing, haplotyping and structural analysis using molecular combing or optical genome mapping. DR1 methylation profiling and whole-exome sequencing (WES) were used as second-line tests in unresolved, borderline, non-contracted or clinically atypical cases.</p><p><strong>Results: </strong>FSHD was confirmed in 121/135 referrals (89.6%): FSHD1 in 109/121 (90.1%), FSHD1+2 in 4/121 (3.3%) and FSHD2 in 8/121 (6.6%). Of the remaining referrals, two had confirmed alternative molecular diagnoses, one had a candidate <i>DES</i>-related myopathy, six were FSHD excluded and five remained unresolved. Single-molecule analysis identified mosaicism, allelic imbalance, homozygous contracted genotypes and complex 4q configurations. Second-line DR1 methylation refined borderline and non-contracted cases, while WES identified six <i>SMCHD1</i> variants, including four identified in this study, and candidate alternative or dual diagnoses. Exploratory analyses showed that age-corrected severity captured repeat length and age-at-onset-related gradients better than raw severity scores.</p><p><strong>Conclusion: </strong>These findings support the real-world diagnostic value of combining established structural, epigenetic and sequencing-based methods for suspected FSHD, particularly in diagnostically challenging referrals. The study further provides cohort-level data from Türkiye, an under-represented population in the FSHD literature, and may inform future diagnostic interpretation of borderline, non-contracted and complex locus configurations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584500","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":"Enrichment of an Ehlers-Danlos-like phenotype in women with the <i>FMR1</i> premutation: a pilot study.","authors":"Emily L Casanova, Caroline B Buchanan, Caleb Hinzman, Layla Johnson, Tofarati Okenimkpe, Alaina Kellum, Tiffany Sheedy, Louise Gane, Elisabeth Makhoul, Randi Hagerman, Paul Hagerman","doi":"10.1136/jmg-2025-111346","DOIUrl":"10.1136/jmg-2025-111346","url":null,"abstract":"<p><strong>Background: </strong>Previous research identified an Ehlers-Danlos (EDS)-like phenotype in fragile X premutation (FXPC) women. This preliminary research examines associations between the presence of this connective tissue phenotype, <i>FMR1</i> genotype and immune-mediated, autonomic-mediated and endocrine-mediated symptoms.</p><p><strong>Methods: </strong>Women with FXPC (n=11; mean age=44 years, SD=9.9) were recruited from Greenwood Genetic Centre and southern Louisiana. Most participants were mothers or close female relatives of individuals with fragile X syndrome. Participants were assessed for hypermobile Ehlers-Danlos syndrome (hEDS) according to the 2017 criteria. They also underwent an active stand test and completed a health-related survey.</p><p><strong>Results: </strong>Observed co-occurrence of this EDS-like phenotype in women with the premutation (n=5) was substantially higher than expected under statistical independence (one-sided OR 15.83, 95% CI 4.67 to 53.65, p=1.119 × 10^-4]. Preliminary data also indicate that FXPC women with <90 <i>FMR1</i> CGG repeats may be at higher risk of developing this phenotype compared with those with >90 repeats (p=0.016, Cohen's d=-1.928). FXPC women with the EDS-like phenotype also reported more immune-mediated symptoms (Benjamini-Hochberg (BH) adjusted p=0.032), a trend towards greater autonomic symptom burden (BH adjusted p=0.054), and had significantly higher supine/standing HR and BP during an active stand test compared with FXPC women without the connective tissue phenotype (p=0.003-0.034).</p><p><strong>Conclusions: </strong>Despite small sample numbers, the observed co-occurrence exceeded expectations under statistical independence and suggests a potential association warranting validation in larger cohorts.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684734","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":"Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial.","authors":"Anurag Saxena, Cheney Jg Drew, Rebecca Cannings-John, Timothy Pickles, Laura J Mills, Emer McDermott, Lianna Angel, Rachel McNamara, Michelle Smalley, Elizabeth Randell, Shelagh K Joss, Deirdre E Donnelly, David Mark Davies, Eleri Owen-Jones, Nigel Kirby, Petrus J de Vries, Kerry Hood, Julian R Sampson","doi":"10.1136/jmg-2026-111529","DOIUrl":"https://doi.org/10.1136/jmg-2026-111529","url":null,"abstract":"<p><strong>Background: </strong>Mammalian target of rapamycin (mTOR) inhibitors are effective treatments for tumours and epilepsy in tuberous sclerosis complex (TSC). This study aimed to determine the effects of the mTOR inhibitor everolimus and a placebo on neuropsychological functioning in TSC.</p><p><strong>Methods: </strong>Individuals with TSC aged 16-60 years and intelligence quotient >60 who scored ≤5th percentile in one or more of 10 memory or executive function variables from the Brain Injury Rehabilitation Trust Memory and Information Processing Battery, the Cambridge Neuropsychological Test Automated Battery and the Test of Everyday Attention were randomised 2:1 to 24 weeks everolimus or placebo and retested at baseline and 4, 12, 24 and 36 weeks. The primary outcome was the proportion of responders, defined as improvement by ≥1 SD in at least one variable.</p><p><strong>Results: </strong>38 participants were randomised, of whom 23 in the everolimus arm and 12 in the placebo arm completed all primary endpoint assessments and were included in outcome analyses. Effect sizes for individual neuropsychological variables were small to medium (Cohen's d=0-0.465), but 20 of 23 (87%, 95% CI 67.9 to 95.5) in the everolimus arm and 9 of 12 (75%, 95% CI 46.8 to 91.1) in the placebo arm were responders. Adverse events were reported in 22/25 (88%) of those randomised to everolimus versus 8/13 (61.5%) for placebo.</p><p><strong>Discussion: </strong>The large proportions of responders in both trial arms may reflect unexpectedly large familiarity, practice or placebo effects in TSC, psychometric issues with parallel test forms and how a response was defined. Our findings may inform the design of future trials of neuropsychological functioning in TSC and similar conditions.</p><p><strong>Trial registration number: </strong>ISRCTN09739757 and NCT01954693.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684718","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>CACNA1C</i> variants associated with focal epilepsy and their correlations with arrhythmias and developmental disorders.","authors":"Yan-Fang Li, Pei Mo, Lan-Zhen Zhang, Xin-Long Zhou, Wen-Yu Zhu, Jun-Hui Zhu, Shu-Hong Liao, Ya-Ting Chen, Weiwen Deng, Dong-Ming Zhang, Xiao-Rong Liu, Yong-Jun Chen, Wei-Ping Liao, Jie Wang, Chuan-Fang Cheng","doi":"10.1136/jmg-2025-110918","DOIUrl":"https://doi.org/10.1136/jmg-2025-110918","url":null,"abstract":"<p><strong>Purpose: </strong><i>CACNA1C</i> variants have been identified in cardiac arrhythmias and developmental disorders (DD). Here, we aimed to explore the association between <i>CACNA1C</i> and epilepsy and the mechanism underlying phenotypic heterogeneity.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed in patients with focal epilepsy. Genes with recurrently identified variants were selected for further studies.</p><p><strong>Results: </strong>Three <i>de novo CACNA1C</i> variants were identified in three patients with focal epilepsy. All variants presented no minor allele frequency in the Genome Aggregation Database, which was significantly lower than that of benign variants in the ClinVar database. The three <i>de novo</i> variants were evaluated as pathogenic or likely pathogenic variants according to the updated American College of Medical Genetics and Genomics (ACMG) classification. Two patients experienced infrequent seizures and became seizure free. The other patient had refractory epilepsy with DD and arrhythmia. Previously, 138 <i>CACNA1C</i> variants were reported to be associated with arrhythmias, of which 39 were classified as pathogenic or likely pathogenic; 30 variants were associated with DD, 19 of which were classified as pathogenic or likely pathogenic according to the updated ACMG classification. Further analysis indicated that null variants were more common in DD than in epilepsy (p=1.39×10^-3) and arrhythmias (p=6.31×10^-7). The epilepsy-associated variants were predominantly located in the voltage sensor region (p=9.03×10^-3), whereas the arrhythmia-associated variants were mostly located in the linker region (p=2.13×10^-4). There was a greater percentage of <i>de novo</i> variants in patients with epilepsy and DD than in those with arrhythmias (p=6.02×10^-3; p=2.47×10^-2).</p><p><strong>Conclusion: </strong><i>CACNA1C</i> is potentially a candidate causative gene of focal epilepsy. The genotype-phenotype correlation of <i>CACNA1C</i> helps explain phenotypic heterogeneity.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684688","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":"The British Society for Genetic Medicine guidance on managing incidental findings identified during rare disease genomic testing.","authors":"Sian Ellard, Helen Hanson, Emma-Jane Cassidy, Kate Thomson, Miranda Durkie, Ian Berry, Kathy Mann, Rachael Mein, Karen Stals, Julia Rankin, Robert W Taylor, Terri P McVeigh, Katie Snape, Clare Turnbull, Tara Clancy, Anneke Lucassen, Zandra C Deans, James Ware, Emma L Baple","doi":"10.1136/jmg-2026-111522","DOIUrl":"https://doi.org/10.1136/jmg-2026-111522","url":null,"abstract":"<p><strong>Background: </strong>Genomic testing will occasionally identify a highly actionable genetic variant or other finding that is not related to the reason for testing. Such incidental findings may be relevant to the patient undergoing testing or to their family members.</p><p><strong>Methods: </strong>This guidance on managing incidental findings was developed by the British Society for Genetic Medicine to support clinicians requesting genomic tests and clinical scientists working in genomic laboratories within the National Health Service.</p><p><strong>Results: </strong>Clinicians should include the possibility of incidental findings with a patient/parent(s) in discussions around genomic testing. Decisions regarding the reporting of a genetic variant unrelated to the referral reason will depend on clinical actionability, penetrance and the variant classification. Pathogenic variants may be reported if there is evidence of high penetrance and available treatment or surveillance that is likely to improve clinical outcome. Testing using large next generation sequencing gene panels and genome-wide array analysis increases the likelihood of revealing heterozygous carrier status for autosomal recessive disorders unrelated to the reason for testing. Reporting incidental heterozygous carrier status for autosomal recessive conditions is not recommended.</p><p><strong>Conclusion: </strong>This guidance provides a framework for the reporting of incidental findings with case examples and a cancer susceptibility gene list. Decision-making in accordance with guidelines will achieve greater consistency than case by case decisions. This guidance may be of use to healthcare professionals in other publicly funded healthcare systems with evolving genomic testing services.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684731","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}