Journal of Medical Genetics最新文献

{"title":"Functional characterisation and pathological significance of variants of <i>MEF2C</i> promoter in tetralogy of Fallot.","authors":"Shao-Jie Wang, Zi-Fei Zheng, Huan-Xin Chen, Qin Yang, Guo-Wei He","doi":"10.1136/jmg-2026-111657","DOIUrl":"10.1136/jmg-2026-111657","url":null,"abstract":"<p><strong>Background: </strong>Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart disease (CHD). The myocyte enhancer factor 2C <i>(MEF2C</i>) transcription factor is a crucial regulator of cardiac development, and variants in the coding region of this gene are a known cause of CHD. However, a significant gap exists in understanding the role of non-coding regulatory variants, specifically those within the <i>MEF2C</i> promoter. This study seeks to fill this gap by investigating whether such promoter variants contribute to TOF pathogenesis and providing functional evidence for their impact.</p><p><strong>Methods: </strong>Targeted sequencing of the <i>MEF2C</i> promoter was performed in 305 TOF patients and 306 controls. Identified rare variants were functionally characterised using dual-luciferase reporter assays in AC16 cardiomyocytes. Bioinformatic predictions and electrophoretic mobility shift assays (EMSA) were applied to assess the impact on transcription factor binding.</p><p><strong>Results: </strong>Five variants (g.24599 G>A, g.24918 T>G, g.25270 T>A (rs904793941), g.25701 C>A and g.25769 T>C (rs886060871)) were identified exclusively in TOF patients. Four of the five variants significantly reduced transcriptional activity at a conservative threshold of p<0.01, with reductions ranging from 56.5% to 87.8% of wild-type. Bioinformatic analysis and EMSA confirmed that these variants alter key transcription factor binding sites (eg, for ETS1, GATA3, NFATC2) and disrupt DNA-protein interactions.</p><p><strong>Conclusion: </strong>This study provides the first functional evidence that <i>MEF2C</i> promoter variants are associated with TOF and affect transcriptional regulation, offering new insights into the potential genetic mechanisms of TOF.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"620-629"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352197","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":"Correction: <i>UK clinical practice guidelines for the management of patients with constitutional <i>POT1</i> pathogenic variants</i>.","authors":"","doi":"10.1136/jmg-2025-110638corr1","DOIUrl":"10.1136/jmg-2025-110638corr1","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"665"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470973","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":"Potential advantage of clinical exome sequencing in <i>BRCA1/2</i>-negative families: a retrospective study of a cohort of 500 patients at a high-risk for hereditary cancers.","authors":"Anastasia Dell'Elice, Claudia Palmarini, Federico Anaclerio, Lucrezia Pilenzi, Giuseppe Calabrese, Chiara Palka, Nicola Tinari, Antonino Grassadonia, Patrizia Ballerini, Simona Grossi, Marco Vitali, Lorenzo Secondi, Paolo Amerio, Valentina Gatta, Liborio Stuppia, Ivana Antonucci","doi":"10.1136/jmg-2026-111497","DOIUrl":"10.1136/jmg-2026-111497","url":null,"abstract":"<p><strong>Background: </strong>Hereditary cancer syndromes (HCSs) account for approximately 5-10% of all cancers and are frequently associated with pathogenic variants (PVs) in genes such as <i>BRCA1</i> and <i>BRCA2</i>. Nevertheless, a substantial proportion of individuals with strong familial cancer aggregation remain genetically unexplained after standard multigene panel testing. Clinical exome sequencing (CES) may overcome this limitation by enabling a broader exploration of cancer susceptibility genes.</p><p><strong>Methods: </strong>This retrospective study included 500 high-risk patients who previously tested negative for <i>BRCA1/2</i> PVs. All samples were analysed using next-generation sequencing technology. Initially, a 60-gene filtered panel recommended by the American Society of Clinical Oncology (ASCO) guidelines was applied, followed by a 102-gene filtered panel derived from CES to identify additional PVs or likely PVs (LPVs) beyond current diagnostic panels. Variant classification was performed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, incorporating ClinGen and gene-specific expert curation recommendations when available.</p><p><strong>Results: </strong>Within the ASCO panel, PV/LPVs were identified in 9% of patients while 35% carried variants of uncertain significance. CES identified additional PVs/LPVs in 5% of patients in genes not currently included in ASCO-recommended surveillance panels, such as <i>RAD50</i>, <i>BLM</i>, <i>WRN</i>, <i>PMS1</i> and <i>FANCA</i>. These variants may represent candidate susceptibility loci requiring further clinical and functional validation.</p><p><strong>Conclusions: </strong>CES may provide additional exploratory genomic information in selected high-risk <i>BRCA1/2</i>-negative patients, particularly when standard panel testing is uninformative. Although many of the additional findings identified are not yet clinically actionable, CES represents a valuable resource for future reinterpretation as gene-disease evidence evolves. Overall, our findings support the use of CES as a second-tier exploratory approach in carefully selected high-risk cases, while emphasising the need for cautious interpretation and continued gene-disease curation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"656-664"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584464","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":"Frequent <i>FBN2</i> variants in pectus excavatum highlight underlying phenotypic variability.","authors":"Xicheng Deng, Yu Zheng, Jinghua Wang, Fang Shen, Jinwen Luo, Cheng Liu, Guihong Yang, Yongjia Yang","doi":"10.1136/jmg-2026-111615","DOIUrl":"10.1136/jmg-2026-111615","url":null,"abstract":"<p><strong>Background: </strong>During genetic screening for radioulnar synostosis (RUS), we identified <i>FBN2</i> variants in individuals who also exhibited pectus excavatum (PE). This study aimed to investigate the association between <i>FBN2</i> variants and non-syndromic paediatric PE.</p><p><strong>Methods: </strong>We phenotyped an <i>Fbn2</i> knockout mouse model. A cohort of 290 paediatric PE probands and their families was recruited. Comprehensive analyses included karyotyping, copy number variation arrays, exome sequencing (ES), Sanger sequencing validation and systematic clinical re-evaluation using the Callewaert scoring system. Statistical burden analysis was performed against 4961 ethnicity-matched ES controls. Gene expression was assessed via fluorescence in situ hybridisation, and Bone Morphogenetic Protein (BMP) signalling activity was examined through immunohistochemistry in murine sternal tissues.</p><p><strong>Results: </strong><i>Fbn2</i>-deficient mice exhibited sternal abnormalities and a PE-like phenotype, without evidence of rib overgrowth. In the human cohort, ES identified 15 rare damaging <i>FBN2</i> variants, including three de novo and three familial cases, distributed across the entire gene. Burden analysis confirmed a significant association between <i>FBN2</i> variants and PE (OR=5.276, 95% CI 2.918 to 9.541, p<0.001). Clinical re-evaluation revealed only mild connective tissue features in carriers, with RUS observed in just one individual. Genotype-phenotype analysis showed minimal overlap between PE and RUS phenotypes, highlighting broad variability. Mechanistically, reduced BMP-SMAD1/5/8 signalling was observed in the sternal ossification centres of <i>Fbn2</i>-mutant mice.</p><p><strong>Conclusion: </strong>Our findings establish <i>FBN2</i> as a significant genetic contributor to isolated PE and underscore the broad phenotypic spectrum and high clinical variability of <i>FBN2</i>-related disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"640-648"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396789","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":"Longest surviving patient with a homozygous splice-altering <i>EGFR</i> pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy.","authors":"Leila Youssefian, Sajjad Biglari, Fatemeh Vahidnezhad, Amir Hossein Saeidian, Rana Samii, Ali Reza Tavasoli, Elnaz Kalamati, Soheila Sotoudeh, Behnaz Bazargani, Sareh Hosseinpour, Neda Pak, Mohammad Amin Tabatabaiefar, Elaheh Malekan Rad, Mehrnaz Mesdaghi, Zahra Saffarian, Fatemeh Saffarian, Alyson Guy, Ariana Kariminejad, John McGrath, Johann E Gudjonsson, Hakon Hakonarson, Hassan Vahidnezhad","doi":"10.1136/jmg-2025-111461","DOIUrl":"10.1136/jmg-2025-111461","url":null,"abstract":"<p><strong>Background: </strong>Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism.</p><p><strong>Methods: </strong>We investigated the genetic cause of a Bartter-like phenotype in an adolescent patient with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalaemia, significantly elevated urine chloride, failure to thrive, and a salt-losing tubulopathy. Additionally, the patient presented with hypergammaglobulinaemia, abnormal cerebral white matter signal changes, skin autoinflammation, and mild intellectual disability.</p><p><strong>Results: </strong>No pathogenic variants were detected in known BS-related genes, and all recessive BS genes were outside regions of homozygosity (ROH) in this patient from a consanguineous family. Instead, exome sequencing and homozygosity mapping identified a homozygous splicing variant, c.2702-2A>G, in the epidermal growth factor receptor (<i>EGFR</i>) gene within an ~28 Mb ROH on chromosome 7p. RNA-Seq and RT-PCR analysis of the patient's RNA confirmed the pathogenicity of this variant, demonstrating aberrant splicing resulting in an in-frame retention of 27 nucleotides from intron 22 of <i>EGFR</i>. Immunofluorescence analysis of the proband's skin revealed a reduced <i>EGFR</i> protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported <i>EGFR</i> variants have been associated with severe neonatal epithelial inflammation, bowel disease, and early mortality, our findings demonstrate that a hypomorphic variant can be compatible with survival into the second decade of life.</p><p><strong>Conclusion: </strong>These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering <i>EGFR</i> pathogenic variant, thereby expanding the phenotypic spectrum of <i>EGFR</i>-associated disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"630-639"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361314","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":"Cancer Variant Interpretation Group UK (CanVIG-UK): updates on an exemplar national subspecialty multidisciplinary network.","authors":"Alice Garrett, Sophie Allen, Charlie F Rowlands, Subin Choi, Miranda Durkie, George J Burghel, Rachel Robinson, Alison Callaway, Joanne Field, Bethan Frugtniet, Sheila Palmer-Smith, Jonathan Grant, Judith Pagan, Trudi McDevitt, Lowri Hughes, Elizabeth Johnston, Laura Yarram-Smith, Peter Logan, Laura Reed, Katie Snape, Helen Hanson, Terri P McVeigh, Clare Turnbull","doi":"10.1136/jmg-2026-111625","DOIUrl":"10.1136/jmg-2026-111625","url":null,"abstract":"<p><strong>Background: </strong>Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017 in response to the publication of the 2015 American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: (1) creation of a national multidisciplinary professional network and regular forum, (2) delivery of training and education, (3) establishment of a consensus approach to the fundamentals of variant interpretation in CSGs, (4) development and ratification of gene-specific frameworks for variant interpretation for CSGs, (5) development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community and (6) facilitation of UK contribution to international variant interpretation endeavours.</p><p><strong>Methods: </strong>A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees.</p><p><strong>Results: </strong>The utility of the CanVIG-UK consensus recommendations for variant interpretation in CSGs was highly rated, with 89/145 (61.4%) of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128 (96.9%) rating it as extremely/very useful. The usage frequency and perceived utility reported for the gene-specific guidance by survey respondents were similar.</p><p><strong>Conclusion: </strong>Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"649-655"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455953","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":"Single-cell transcriptomics identifies neural fate disruption and glial reprogramming caused by <i>RARS2</i> deficiency.","authors":"Xing Wei, Jing Wang, Yanyun Wang, Cong Zhou, Zhaoyi Chen, Shanling Liu, Huaqin Sun, Bin Zhou, Lin Zhang","doi":"10.1136/jmg-2025-111413","DOIUrl":"10.1136/jmg-2025-111413","url":null,"abstract":"<p><strong>Background: </strong>Pontocerebellar hypoplasia type 6 (PCH6) is caused by biallelic pathogenic variants in <i>RARS2</i>, encoding mitochondrial arginyl-tRNA synthetase. Although mitochondrial dysfunction is a recognised feature, how <i>RARS2</i> deficiency disrupts neural lineage development remains unclear.</p><p><strong>Methods: </strong>We generated <i>rars2</i>-deficient zebrafish using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system and performed single-cell RNA sequencing (scRNA-seq) at 48 hours postfertilisation, complemented by immunofluorescence, in situ hybridisation, behavioural assays and ultrastructural analyses. Neural lineage composition, developmental trajectories, intercellular communication and transcriptional programmes were systematically examined.</p><p><strong>Results: </strong><i>rars2</i> ^<i>-/-</i> zebrafish displayed impaired survival, locomotor deficits, early mitochondrial ultrastructural damage and marked disruption of neurogenesis. scRNA-seq revealed reduced neuronal populations and expansion of neural progenitor and glial-like cells. Key neurogenic regulators (<i>neurod4</i>, <i>her6</i> and <i>pou3f1</i>) were downregulated, whereas glial and stress-associated markers (<i>hmgb1a, fabp7a</i> and <i>foxp1b</i>) were upregulated. Developmental pathways including Notch and non-canonical Wnt were attenuated while extracellular matrix (ECM), adhesion and inflammatory programmes were activated. Additional trajectory-based analyses supported dysregulated lineage progression characterised by glial programme activation and impaired maintenance of neurogenic differentiation.</p><p><strong>Conclusion: </strong><i>RARS2</i> deficiency disrupts mitochondrial integrity and reprograms neural lineage development through coordinated suppression of neurogenic transcriptional networks and activation of glial/ECM programmes. These findings provide mechanistic insight into loss-of-function <i>RARS2</i> deficiency and highlight candidate molecular pathways for future therapeutic investigation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"683-695"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630630","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":"Unified genetic risk score for prostate cancer enables improved risk stratification for clinical decision-making.","authors":"Zhuqing Shi, Ashley J Mulford, Jun Wei, Huy Tran, Annabelle Ashworth, Siqun Lilly Zheng, Jim Lu, Alan R Sanders, Brian Helfand, Jianfeng Xu","doi":"10.1136/jmg-2026-111746","DOIUrl":"10.1136/jmg-2026-111746","url":null,"abstract":"<p><strong>Background: </strong>Current clinical approaches to inherited prostate cancer (PCa) risk rely on binary classification of pathogenic variant (PV) carrier status without accounting for gene-specific heterogeneity or polygenic risk. We developed an integrated genetic risk model reflecting a continuum of inherited susceptibility.</p><p><strong>Methods: </strong>In the UK Biobank (UKB; n=218 484), we evaluated associations of PVs in 11 clinically recommended genes and a polygenic risk score (PRS) with incident PCa using Cox models. A continuum model (GenProb-PCa) incorporating gene-specific PVs and PRS was developed and compared with binary PV-based models. Model performance was assessed using discrimination, calibration and continuous net reclassification index (cNRI). External validation was performed in a health system cohort, the Genomic Health Initiative (GHI; n=6590).</p><p><strong>Results: </strong>Five genes (<i>ATM</i>, <i>BRCA2</i>, <i>CHEK2</i>, <i>HOXB13</i>, <i>MSH2</i>) and the PRS were independently associated with PCa risk (all p<0.001) in UKB. Compared with binary models, GenProb-PCa demonstrated superior discrimination (C-index 0.69 vs 0.52; p<0.001), with significant improvement in reclassification (cNRI 0.58; p<0.001). Findings were validated in GHI using the UKB-derived coefficients (C-index 0.64 vs 0.54, p<0.001; cNRI 0.31, p<0.001). Compared with binary PV-based models, 20% of non-PV carriers were reclassified to higher risk groups and 60% of carriers to lower risk groups. The model identified individuals at markedly elevated lifetime risk, with cumulative incidence exceeding 20% by age 75 among the top 8% of the distribution.</p><p><strong>Conclusions: </strong>An integrated continuum genetic risk model, GenProb-PCa, improves PCa risk stratification beyond binary approaches by capturing heterogeneity in inherited risk. This framework may enable more precise risk-based screening strategies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"676-682"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620370","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":"Rapid minigene workflow for functional reclassification of splicing variants in hereditary cancer diagnostics.","authors":"Noemi Calandra, Elisabetta Mereu, Paola Ogliara, Guido Casalis Cavalchini, Daniela Francesca Giachino, Mirko Parasiliti Caprino, Giorgia Gai, Alessandro Mussa, Stefano Vallero, Enrico Grosso, Andrea Zonta, Franca Fagioli, Matteo Ruggiu, Barbara Pasini, Roberto Piva","doi":"10.1136/jmg-2026-111675","DOIUrl":"10.1136/jmg-2026-111675","url":null,"abstract":"<p><strong>Background: </strong>Next-generation sequencing of cancer predisposition genes is routinely used in hereditary cancer diagnostics. However, a substantial fraction of detected variants remains clinically unresolved. Using a customised 77-gene panel, we analysed 2142 individuals and identified 384 pathogenic or likely pathogenic variants across 54 genes, corresponding to a diagnostic yield of approximately 18%. Despite this, 17% of cases carried variants of uncertain significance, many of which were suspected to affect pre-mRNA splicing and are particularly challenging to interpret due to the limited reliability of in silico predictions and lack of experimental evidence.</p><p><strong>Methods: </strong>To address this diagnostic gap, we developed a streamlined minigene-based workflow for rapid functional evaluation of splicing variants and applied it retrospectively. The approach relies on synthetic DNA and recombination-based cloning, eliminating the need for patient-derived RNA and enabling efficient construct generation within a clinically compatible timeframe. Computational prioritisation using AlphaGenome was integrated to support variant selection, while experimental assays provided direct evidence of splicing outcomes.</p><p><strong>Results: </strong>Application of this strategy allowed the reclassification of previously unresolved variants and clarified cases with discordant computational evidence. Importantly, the workflow is designed for implementation in routine diagnostic settings, with a turnaround time aligned with clinical reporting requirements.</p><p><strong>Conclusion: </strong>This approach provides a robust and scalable framework for functional interpretation of splicing variants, improving diagnostic resolution and supporting more informed clinical decision-making in hereditary cancer genetics.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"666-675"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818655","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":"Inherited retinal disease genes with dual inheritance patterns: insights from the IRD-PT registry.","authors":"Mariana Ferreira Francisco, Beatriz Gaspar, Rufino Silva, Ana Luísa Carvalho, João Pedro Marques","doi":"10.1136/jmg-2026-111618","DOIUrl":"10.1136/jmg-2026-111618","url":null,"abstract":"<p><strong>Background: </strong>Inherited retinal diseases (IRDs) typically follow a single inheritance pattern, but some genes cause disease through both autosomal recessive (AR) and autosomal dominant (AD) patterns, challenging genetic counselling. This study aims to identify dual inheritance genes in a Portuguese cohort and characterise the prevalence of each inheritance mode and associated phenotypes.</p><p><strong>Methods: </strong>Cross-sectional study at Portugal's largest IRD referral centre. Genes reported with dual inheritance were identified through literature search and screened in IRD-PT registry. For each gene, AR versus AD proportion was determined and clinical features were analysed to establish genotype-phenotype correlations.</p><p><strong>Results: </strong>Among 40 genes reported with dual inheritance, 22 were present in the IRD-PT registry and nine displayed both patterns (102 families, 141 patients). <i>PRPH2</i> (95.0% AD) was associated with retinitis pigmentosa (RP) and macular dystrophies. <i>ABCC6</i> (91.3% AR) was linked to pseudoxanthoma elasticum (PXE). <i>BEST1</i> (91.7% AD) mainly caused Best disease, while <i>PROM1</i> (76.9% AR) was linked to RP, macular dystrophy and cone-rod dystrophy. <i>PRPF31</i> (88.9% AD) was exclusively associated with RP. <i>IMPG2</i> (75.0% AR) and <i>IMPG1</i> (87.5% AD) caused RP and adult-onset vitelliform macular dystrophy. <i>NR2E3</i> (85.7% AR) was linked to enhanced S-cone syndrome and RP, and <i>RP1</i> was detected in two families (one AR, one AD), presenting with RP.</p><p><strong>Conclusions: </strong>Dual inheritance genes accounted for 12% of our genetic diagnoses. This spectrum, modulated by variant location and allele dosage, determines phenotypes and contributes to IRD heterogeneity. Deep phenotyping and comprehensive molecular diagnosis are essential for accurate genetic counselling and patient management.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"613-619"},"PeriodicalIF":3.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283697","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}