Journal of Medical Genetics最新文献

{"title":"Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.","authors":"Valentina Trevisan, Germana Viscogliosi, Lucrezia Perri, Chiara Ritarossi, Francesco Cerza, Roberta Pastorino, Maria Grazia Pomponi, Roberta Onesimo, Valentina Giorgio, Roberta De Angelis, Cristian Bisanti, Donato Rigante, Elisabetta Flex, Antonio Ruggiero, Maurizio Genuardi, Marco Tartaglia, Giuseppe Zampino, Simone Martinelli, Chiara Leoni","doi":"10.1136/jmg-2026-111658","DOIUrl":"10.1136/jmg-2026-111658","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined.</p><p><strong>Methods: </strong>We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations.</p><p><strong>Results: </strong>In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying <i>PTPN11</i> variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in <i>HRAS</i>, <i>PTPN11</i> and <i>SOS1</i> genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers.</p><p><strong>Conclusion: </strong>Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919275","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":"Prophylactic total gastrectomy in germline <i>CDH1</i> carriers: results across 25 years from a systematic review and meta-analysis.","authors":"Giovanni Corso, Giovanni Quadrini, Vincenzo Bagnardi, Carlo La Vecchia","doi":"10.1136/jmg-2026-111804","DOIUrl":"https://doi.org/10.1136/jmg-2026-111804","url":null,"abstract":"<p><strong>Background: </strong>Prophylactic total gastrectomy (PTG) is a risk-reducing strategy considered in individuals at high risk for diffuse gastric cancer (DGC) associated with germline <i>CDH1</i> pathogenic variants.</p><p><strong>Methods: </strong>A systematic literature search (PubMed, Scopus) was conducted to identify studies that performed PTGs in <i>CDH1</i> carriers. Data were analysed using a random-effects generalised linear mixed model. Cochran's Q test was used to assess the heterogeneity between studies. Forest plots were used to display study-specific estimates, and the pooled estimates were calculated within three subsequent cohort periods (2001-2010; 2011-2020; 2021-2025). Statistical analyses were performed using R software.</p><p><strong>Results: </strong>A total of 21 studies were considered out of 302 originally identified, including a total of 967 <i>CDH1</i> carriers. PTG was performed in 62.9% of <i>CDH1</i> pathogenic variant carriers. Advanced DGC (>pT1a) was detected in 1.1% and ≤pT1a in 79% in postoperative PTG specimens. The majority of PTGs were reported from North America (58.9%). The pooled proportion of PTG decreased from 83.2% (95% CI 61.0% to 94.0%) in 2001-2010 to 71.0% (95% CI 59.0% to 80.7%) in 2011-2020 and to 67.5% (95% CI 48.9% to 81.8%) in 2021-2025 (p for trend=0.12).</p><p><strong>Conclusion: </strong>About 60% of PTGs were reported from North America. The majority of the lesions were classified as pT1a. PTG indication has been progressively and constantly decreasing during the last years considered. This can be related to the recent genetic analyses reporting a lower DGC risk in <i>CDH1</i> carriers and with the improvement in detection of early lesions during endoscopy.</p><p><strong>Prospero registration number: </strong>CRD420261368873.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017046","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":"Evaluating consistency and variation in mainstream germline cancer genetic and genomic testing.","authors":"Agnes Sebastian, Elaine Suk-Ying Goh, Lianna Kyriakopoulou","doi":"10.1136/jmg-2026-111749","DOIUrl":"https://doi.org/10.1136/jmg-2026-111749","url":null,"abstract":"<p><strong>Background: </strong>Mainstreaming, in which genetic testing is shifted outside clinical genetics, can improve access to genetic testing. This is being explored in several countries, including Canada, the USA and the UK. However, standardised practice within a jurisdiction helps ensure equitable high-quality access. This study aimed to evaluate consistency in the implementation of cancer genetics mainstreaming across Ontario, Canada.</p><p><strong>Methods: </strong>Adult cancer genetics centres in Ontario were emailed an online survey in June 2025, which was completed by mainstreaming implementation leads. Results were anonymised and analysed in aggregate.</p><p><strong>Results: </strong>Of 18 centres contacted, 13 responded; 12/13 reported having implemented cancer genetics mainstreaming. All mainstreaming centres offered pathways for breast, ovarian, prostate and pancreatic cancers, primarily based on personal history criteria. Most centres did not mainstream for other cancer sites but were planning to expand. A 19-gene hereditary breast/ovarian/prostate panel was most commonly ordered. There was variation in the timepoint of genetics service involvement. Turnaround times for expedited results were relatively consistent (median 21 days, IQR 18-22), whereas turnaround times for routine results varied widely (median 50 days, IQR 36-94).</p><p><strong>Conclusion: </strong>Across Ontario, centres were generally consistent in mainstreaming the most common indications. Opportunities to improve quality and equity include reducing variability in routine turnaround time, standardising management pathways for negative results and streamlining ordering to align with eligibility criteria. Some centres cited limited genetics knowledge as an implementation barrier, though engagement improved over time. Ongoing evaluation of mainstreaming can support consistent access to care.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017043","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":"Safety and efficacy of AAV-based mini- and micro-dystrophin gene therapies in Duchenne muscular dystrophy: a systematic review and meta-analysis of clinical trials.","authors":"Haya Nassour, Samer A Al Shbailat, Arwa Sobhi Ibrahim, Amal Mohammad Allan, Mostafa Saad Badie Aboudeeb, Qais M Alnjoom, Mohammad Jebril Farhan Alrfou, George Elian Makhoul, Mahmoud Ghassan Weis, Rasha K Ahmad, Sara M Abdelstar","doi":"10.1136/jmg-2026-111649","DOIUrl":"https://doi.org/10.1136/jmg-2026-111649","url":null,"abstract":"<p><strong>Background: </strong>Adeno-associated virus (AAV)-mediated mini- and micro-dystrophin gene therapies have emerged as promising treatments for Duchenne muscular dystrophy (DMD), yet their overall efficacy and safety remain uncertain.</p><p><strong>Objective: </strong>To systematically evaluate and quantitatively synthesise clinical evidence on the efficacy and safety of AAV-based gene therapies in DMD.</p><p><strong>Methods: </strong>A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Five databases were searched from inception to November 2025. Clinical trials reporting functional and/or safety outcomes were included. Random-effects meta-analyses were performed for comparable outcomes. The study protocol was prospectively registered on PROSPERO.</p><p><strong>Results: </strong>Nine studies (six trials; n=218) were included, with four contributing to the meta-analysis. Delandistrogene moxeparvovec improved North Star Ambulatory Assessment (NSAA) scores by +3.08 points at 1 year (95% CI 1.85 to 4.32), with greater effects in 4-5 year-olds (+4.06) than in 6-7 year-olds (+1.01). Improvements from baseline were observed in time to rise (-0.29 s) and four-stair climb (-0.48 s) but not in 10 or 100 m walk/run. Compared with controls, a significant effect was observed only for time to rise (-0.64 s), with no differences in NSAA or other timed tests. Effects were more consistent in younger patients. Fordadistrogene movaparvovec showed smaller effects. Most patients experienced treatment-related adverse events, mainly mild and transient; however, serious events, including hepatotoxicity and rare fatal outcomes, occurred.</p><p><strong>Conclusions: </strong>AAV-based gene therapies provide modest functional benefits in ambulatory boys with DMD, particularly at younger ages, but carry important safety risks. Larger trials with longer follow-up are needed to clarify long-term efficacy and optimise risk-benefit profiles.</p><p><strong>Prospero registration number: </strong>CRD420261293429.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982857","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":"Phenotypic manifestations and variant reclassification of germline <i>PTEN</i> variants: a nationwide Danish study.","authors":"Annette Lyngholm Sandsdalen, Anne Marie Jelsig, Birgitte Bertelsen, Zuzana Lohse, Annabeth Hogh Petersen, Maja Smerdel, Inge Sokilde Pedersen, Malene Lundsgaard, Lise Lotte Christensen, Charlotte Lautrup, Susanne Eriksen Boonen, Mads Thomassen, Karin A W Wadt, Thomas van Overeem Hansen","doi":"10.1136/jmg-2026-111772","DOIUrl":"https://doi.org/10.1136/jmg-2026-111772","url":null,"abstract":"<p><strong>Background: </strong>Classification of heterozygous germline <i>PTEN</i> variants in patients with, or suspected of having, <i>PTEN</i> hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance.</p><p><strong>Methods: </strong>We identified all patients with a <i>PTEN</i> variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest <i>PTEN</i> gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed.</p><p><strong>Results: </strong>167 patients from 112 families were enrolled. Eighty-seven unique <i>PTEN</i> variants were identified, including 20 novel variants. After applying the <i>PTEN</i> gene<i>-</i>specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 <i>PTEN</i> variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients.</p><p><strong>Conclusion: </strong>We identified 87 different <i>PTEN</i> variants, and application of <i>PTEN</i> gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919977","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":"Hypertrophic cardiomyopathy: a genome-wide association meta-analysis and polygenic risk score.","authors":"Luis R Lopes, Nay Aung, Stefan Van Duijvenboden, Hannah L Nicholls, Richard Burns, Joanna Jager, Massimiliano Lorenzini, Mohammed Majid Akhtar, Alexandros Protonotarios, Cayetana Barbeito-Caamaño, Jose María Larrañaga-Moreira, Roberto Barriales-Villa, Kayesha Coley, Chiara Batini, Gerald Sze, Martin D Tobin, Catherine John, Steffen E Petersen, Petros Syrris, Patricia B Munroe, Perry M Elliott","doi":"10.1136/jmg-2026-111722","DOIUrl":"https://doi.org/10.1136/jmg-2026-111722","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes stratified by genotype status.</p><p><strong>Methods: </strong>A discovery genome-wide association study (GWAS) was performed on 2284 HCM cases and 4525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with HCM diagnosis in 411 213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation); and sudden cardiac death (SCD) in 1756 HCM cases. PRS analyses were stratified by genotype status.</p><p><strong>Results: </strong>Three loci were found in the discovery GWAS (<i>BAG3</i>, <i>FHOD3</i> and novel locus <i>PPP1R3A</i>). In the meta-analyses, 70 unique loci were identified, four novel (<i>MYPN, YWHAE, NOS1AP</i> and <i>OBSCN</i>). Bioinformatic analyses identified <i>NOS1AP</i> as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (HR=3.19, 95% CI 2.46 to 4.14 for top 5% vs lower 95%; HR=1.88, 95% CI 1.72 to 2.06 per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Genotype-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR=2.72, 95% CI 1.03 to 7.17).</p><p><strong>Conclusions: </strong>We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892037","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":"Exome sequencing and large-scale analysis of electronic medical record-linked biobank data identify candidate deafness genes.","authors":"Zippora Brownstein, Lara Kamal, Yazeed Zoabi, Keren Gesin, Hadas Knoller, Shadi Khoury, Roni Hahn, Sapir Brand, Daphna Marom, Hagit Shani, Nada Danial-Farran, Stavit Shalev, Varda Shalev, Asaf Peretz, Tal Patalon, Noam Shomron, Karen B Avraham","doi":"10.1136/jmg-2026-111784","DOIUrl":"https://doi.org/10.1136/jmg-2026-111784","url":null,"abstract":"<p><strong>Introduction: </strong>Rapid advances in whole-exome sequencing (WES) have enabled large-scale detection of pathogenic variants. Although hundreds of genes are implicated in hearing loss, up to half of inherited cases remain unsolved, limiting eligibility for gene therapy trials that require genetic diagnosis. Biobanks and electronic medical records (EMRs) offer opportunities to integrate genomic and clinical data at scale and expand the spectrum of hearing loss genes. Despite clinical value, EMRs often lack key information such as inheritance patterns, posing challenges for accurate interpretation.</p><p><strong>Methods: </strong>WES was performed on DNA samples from 1038 hearing-impaired patients enrolled in the Maccabi Research and Innovation Center Tipa Biobank. Clinical data were extracted from EMRs. Audiograms were available for all cases, although data on age of onset, family history and mode of inheritance were mostly unavailable. We applied a scalable bioinformatics analysis strategy for high-throughput annotation, filtering and prioritisation of WES variants across more than 1000 patients, designed to accommodate incomplete and heterogeneous clinical records.</p><p><strong>Results: </strong>Using this approach, 15% of cases were solved or potentially solved through known or novel variants in established deafness genes. Homozygous variants in novel candidate genes were identified in 3% of cases. Functional characterisation was performed for promising candidate genes to validate their role in the ear.</p><p><strong>Conclusion: </strong>These findings demonstrate that WES can determine disease aetiology in large, genetically heterogeneous populations, even in the context of incomplete clinical data. This approach supports large-scale genetic screening and provides a framework for identifying patients who may benefit from emerging gene-based therapies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887711","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":"Exploring the clinical and mutational spectrum of <i>MORC2</i>-associated disorders.","authors":"Aysylu Murtazina, Eugenii Tatarsky, Iuliia Viakhireva, Artem Borovikov, Alexandra Filatova, Elena Dadali, Nina Demina, Natalia Semenova, Tatiana Markova, Ludmila Bessonova, Dmitrii Subbotin, Bakhytkul Myrzaliyeva, Marcello Scala, Kameryn Butler, Cyril Mignot, Hannah Moore, Neena Champaigne, Arnaud Isapof, Valeria Capra, Claudio Bruno, Federico Zara, Romano Tenconi, Ilya Kanivets, Andrey Marakhonov, Olga Shchagina, Timofei Vizerov, Philipp Sviridov, Oxana Ryzhkova, Sergey Kutsev, Mikhail Skoblov","doi":"10.1136/jmg-2025-110787","DOIUrl":"https://doi.org/10.1136/jmg-2025-110787","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic missense variants in the <i>MORC2</i> gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals.</p><p><strong>Methods: </strong>Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level.</p><p><strong>Results: </strong>A total of 11 different missense variants in the <i>MORC2</i> gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases.</p><p><strong>Conclusion: </strong>A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the <i>MORC2</i> gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850499","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":"Unmasking NF1 mosaicism: optical genome mapping identifies a novel t(15;17) translocation in melanocytes.","authors":"Joséphine Blancke, Suzanne Vanhauwaert, Stijn Van de Sompele, Kathleen Bm Claes, Bert Callewaert, Lien Depaepe, Sandra Janssens, Sofie De Schepper, Siebe Loontiens, Lore Pottie, Aude Beyens","doi":"10.1136/jmg-2026-111525","DOIUrl":"10.1136/jmg-2026-111525","url":null,"abstract":"<p><p>Mosaic neurofibromatosis type 1 (NF1) poses a significant diagnostic challenge due to low-level mosaicism and the confinement of pathogenic variants to neuroectodermal lineages, frequently resulting in false-negative findings when testing is limited to peripheral blood. At present, molecular confirmation of NF1 often relies on the detection of pathogenic variants in tumour tissue. However, many young individuals present exclusively with benign pigmentary manifestations, such as café-au-lait macules and freckling, and therefore lack accessible tumour material. Molecular analysis of pigmentary lesions is technically challenging because skin biopsies contain only a small proportion of melanocytes, which particularly hampers the detection of low-level copy number and structural variants using conventional diagnostic approaches.We report a young woman referred for reproductive counselling who presented with unilateral pigmentary lesions suggestive of mosaic NF1, in whom a combined approach using melanocyte culture and optical genome mapping identified a reciprocal balanced translocation disrupting the <i>NF1</i> locus, t(15;17)(q26.1;q11.2), representing the molecular predisposing event. To our knowledge, this is the first report of a reciprocal translocation in mosaic NF1, highlighting the role of structural genomic rearrangements in this disorder and underscoring the diagnostic utility of optical genome mapping in suspected cases. Molecular confirmation of mosaic NF1 is critical for accurate diagnosis, clinical management, and genetic counselling.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"573-577"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147963985","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":"Review of estimates of birth incidence and population prevalence over time and between countries of the rare neurodevelopmental condition Prader-Willi syndrome.","authors":"Joyce Whittington, Anthony J Holland","doi":"10.1136/jmg-2025-111438","DOIUrl":"10.1136/jmg-2025-111438","url":null,"abstract":"<p><p>Epidemiological data such as birth incidence or population prevalence for rare conditions is difficult to obtain because of the large sample size required in order to obtain a valid estimate (ie based on a reasonable number of cases) and the difficulty of either identifying all cases or meeting the cost and logistics of screening the whole general population in that large sample. This article illustrates these difficulties in the case of the rare neurodevelopmental condition Prader-Willi syndrome (PWS). Before reviewing attempts that have been made over the years to estimate birth incidence and/or population prevalence in this condition, this review discusses aspects of PWS, clear definitions of the measures themselves and aspects of general populations that are pertinent to estimates of birth incidence and population prevalence. Although most published studies on PWS quote a prevalence (meaning not always clear) estimate, very few quote the original study on which it is based. Our review found very few (12) original studies. These are described in some detail and where relevant methodological details that render the findings suspect are discussed. Finally, we answer the question of the existence of global estimates for birth incidence and population prevalence of PWS, showing that they will vary from one population to another at a given time and from one time period to another for a given population. However, for very similar populations at a given time, the values may lie within a very close range.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"543-547"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175940","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}