Journal of Medical Genetics最新文献

{"title":"Expanded carrier screening in a Southwestern Chinese population indicates East Asian specific low-frequency pathogenic variants account for nearly half of the at-risk couple rate.","authors":"Sha Liu, Liyuan Cao, Victor Wei Zhang, Shuang Huang, Haipeng Liu, Xiang Wei, Yuan Luo, Yue Li, Lin Zhou, Linzhi Jiang, Qian Zhu, Hongqian Liu","doi":"10.1136/jmg-2025-111273","DOIUrl":"https://doi.org/10.1136/jmg-2025-111273","url":null,"abstract":"<p><strong>Background: </strong>The optimal disease spectrum for carrier screening (CS) remains debated. We aimed to characterise the carrier landscape and quantify the at-risk couple rate (ACR) components in a Chinese population to guide panel design.</p><p><strong>Methods: </strong>Using a 334-gene expanded CS panel, we screened 3748 individuals from Sichuan, China. Pathogenic/likely pathogenic (P/LP) variants were classified by allele frequency and geographic specificity.</p><p><strong>Results: </strong>Overall, 65.55% of participants carried at least one P/LP variant. We identified 83 at-risk couples (ACR 5.19%), including 55 couples at risk for autosomal recessive (AR) disorders. We catalogued 1372 P/LP variants for AR conditions. Notably, 46 variants were classified as low frequency (minor allele frequency ≥0.1%). Among these 46 low-frequency variants, 54% (25/46) were identified as East Asian-specific. Strikingly, these 25 East Asian-specific variants contributed 41.8% (23/55) to the AR at-risk couples, whereas 11 globally shared alleles contributed only 9.1%. Three regionally enriched variants in <i>HBB</i>, <i>GJB2</i> and <i>SLC25A13</i> alone contributed 20% to the AR ACR.</p><p><strong>Conclusion: </strong>East Asian-specific low-frequency variants significantly contribute to the carrier burden in this population, accounting for nearly half of the AR risk. These findings provide empirical evidence that CS panels should prioritise population-specific carrier frequencies over global data to maximise clinical utility in regions with specific ethnic compositions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615748","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":"Long-read sequencing enables trio-assisted phasing of <i>de novo</i> variants in the imprinted gene <i>MAGEL2</i>.","authors":"Thomas W Laver, Preeah Sangha, Lucy Mallin, Michal Cohen, Yağmur Ünsal, Huseyin Demirbilek, Matthew N Wakeling, Jasmin J Bennett, Jayne A L Houghton, Jonna M E Männistö, Emma Dempster, Sarah E Flanagan","doi":"10.1136/jmg-2025-111282","DOIUrl":"https://doi.org/10.1136/jmg-2025-111282","url":null,"abstract":"<p><p>Schaaf-Yang syndrome and Prader-Willi syndrome are imprinting disorders that result from the disruption of paternally expressed genes within the 15q11-q13 region. Both conditions present with overlapping clinical features including developmental delay, hypotonia and endocrine abnormalities. Schaaf-Yang syndrome specifically results from heterozygous variants in the paternally expressed <i>MAGEL2</i> gene. Because these variants are often <i>de novo</i>, determining that the variant is on the paternal allele is essential for a definitive diagnosis. Traditional methods, such as methylation-specific PCR, are labour-intensive, while it is challenging to phase variants separated by distances greater than the fragment length (~600 bp) using short-read sequencing. In this study, we used long-read Oxford Nanopore sequencing to perform trio-assisted phasing of a <i>de novo MAGEL2</i>, p.(Gln638Ter) variant identified in two unrelated probands referred for congenital hyperinsulinism genetic testing. Long reads spanning both the variant and informative parental heterozygous variants confirmed that the variant was on the paternal allele and was therefore pathogenic and causative of Schaaf-Yang syndrome and associated with hyperinsulinism in both individuals. Our findings demonstrate the clinical utility of long-read sequencing for enabling trio-assisted variant phasing in imprinting disorders, particularly when phenotypes are incomplete or overlapping. Our findings further highlight congenital hyperinsulinism as a rare but important feature associated with Schaaf-Yang syndrome.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592657","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 SINEs were there: identification of a pathogenic Alu insertion in a patient with DICER1-related tumour predisposition.","authors":"Oluwatosin O Taiwo, Paola Angelini, Iman Awadh, Celine Domecq, William D Foulkes, Hood Mugalaasi, Henry Cope, Iryna Stasevich, Samuel E D Lawrence, Avgi Andreou, Suzanne Macmahon, Mikel Valganon-Petrizan, Helen Hanson","doi":"10.1136/jmg-2025-111365","DOIUrl":"https://doi.org/10.1136/jmg-2025-111365","url":null,"abstract":"<p><p><i>DICER1</i>-related tumour predisposition (DRTP) is an autosomal dominant disorder marked by increased risk of benign and malignant tumours across multiple organ systems. A genetic diagnosis of DRTP requires identification of a (likely) pathogenic germline <i>DICER1</i> variant to confirm the diagnosis, and guide clinical management, including cascade testing and surveillance of at-risk relatives.We report a 14-year-old girl who developed multiple <i>DICER1</i>-associated tumours with high clinical suspicion of DRTP. Initial testing via next-generation sequencing and whole genome sequencing revealed only hotspot somatic <i>DICER1</i> variants, with no detectable germline variant, complicating the genetic diagnosis.A structural variant (SV) initially detected in a tumour sample prompted retrospective review of alignment data from all previously tested tumour, blood and normal tissue samples. This revealed a consistent SV across all samples. Short-read data suggested the SV was an Alu element insertion within the RNase IIIa domain of DICER1, but read length was insufficient for conclusive characterisation.Subsequent long-read nanopore sequencing confirmed a pathogenic AluY insertion, predicted to disrupt DICER1 function.This case highlights the importance of comprehensive genomic and functional analyses, especially in unresolved cases with strong clinical suspicion. It also demonstrates the value of long-read sequencing in identifying complex variants missed by conventional approaches.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592609","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":"Molecular sleuthing: unmasking hidden lymphomas through plasma DNA sequencing.","authors":"Mathilde Bonnot, Pauline Bertin, Thibault Maillet, Nicolas Guyotat, Julliane Bloch, Steeve Chevreux, Isabelle Mosnier, Hervé Ghesquières, Audrey Pechenot, Virginie Desestret, Pierre Sujobert, Sarah Huet","doi":"10.1136/jmg-2025-111458","DOIUrl":"https://doi.org/10.1136/jmg-2025-111458","url":null,"abstract":"<p><p>Diagnosing lymphomas can be challenging, particularly in atypical presentations lacking histological confirmation. We report two cases where next-generation sequencing of plasma cell-free DNA (cfDNA) enabled the early detection of diffuse large B-cell lymphoma, months before biopsy confirmation. cfDNA analysis identified key lymphoma-associated mutations, guiding diagnosis when conventional investigations were inconclusive. These findings highlight cfDNA's potential as a non-invasive diagnostic tool for occult lymphoma. While further validation is needed, cfDNA may facilitate earlier intervention in challenging cases, improving patient outcomes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592603","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>ATM</i> c.7374_7375insAlu is a French-Canadian founder pathogenic variant associated with predisposition to pancreatic and breast cancer.","authors":"Yifan Wang, Celine Domecq, Adeline Cuggia, Alejandro Mejia-Garcia, Joan Miguel Romero, Nancy Hamel, Rejean Lapointe, Diane Provencher, Anne-Marie Mes-Masson, Patricia N Tonin, Simon Gravel, George Zogopoulos, William D Foulkes","doi":"10.1136/jmg-2025-111441","DOIUrl":"https://doi.org/10.1136/jmg-2025-111441","url":null,"abstract":"<p><p>Founder pathogenic variants (PVs) in <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> increase lifetime risk of developing breast (BC), ovarian (OC) and pancreatic (PC) cancer. They have been identified in French-Canadians (FC), a population exhibiting genetic drift due to common ancestral origins. PVs in <i>ATM</i> also increase BC and PC risk; however, <i>ATM</i> founder PVs have not been described in FCs. Here, we report the identification of a germline <i>ATM</i> c.7374_7375insAlu in a FC family with BC and PC. Using a case-control study of 19 852 FC individuals, we show that heterozygous carriers of this variant are more prevalent in PC cases versus controls (6/325 (1.85%) vs 28/18 129 (0.15%), p<0.001) and BC cases versus female controls (5/858 (0.58%) vs 13/9768 (0.13%), p<0.001). There was no difference in the prevalence of heterozygous carriers in patients with endometrial cancer or OC compared to controls. <i>ATM</i>c.7374_7375insAlu carriers share a common haplotype, suggesting that the variant was inherited from a common FC ancestor, which originated approximately 10.53 generations (305 years) ago. Taken together, this study identifies <i>ATM</i> c.7374_7375insAlu as a novel FC founder PV that contributes to PC and BC predisposition. Improving carrier detection may identify at-risk relatives who may benefit from cancer-directed surveillance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592691","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":"Damaging missense variants in innate immunity genes are associated with earlier age of breast cancer onset in <i>BRCA1</i> 185delAG carriers.","authors":"Sapir Shemesh, Rinat Bernstein-Molho, Shelley Shoval, Yael Laitman, Dana Madorsky-Feldman, Eitan Friedman, Ran Elkon","doi":"10.1136/jmg-2025-111394","DOIUrl":"https://doi.org/10.1136/jmg-2025-111394","url":null,"abstract":"<p><strong>Background: </strong>Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in <i>BRCA1</i> is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among <i>BRCA1</i> PV carriers, indicating that further genetic modifiers remain to be identified.</p><p><strong>Methods: </strong>Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the <i>BRCA1</i> 185delAG founder PV.</p><p><strong>Results: </strong>In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set <i>NATURAL_KILLER_CELL_ACTIVATION</i> was 3.62 (95% CI 1.96 to 6.67; p=3.8×10^-5).</p><p><strong>Conclusion: </strong>These findings highlight a potential role for innate immune pathways as modifiers of <i>BRCA1</i> penetrance and support the development of more refined, personalised risk prediction models.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592615","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":"Perspectives of adolescents and young adults with advanced cancer on complete genomic analysis in standard oncology care.","authors":"Lina H Lankhorst, Milou J P Reuvers, Noor A A Giesbertz, Lizet E van der Kolk, Helle-Brit Fiebrich-Westra, Mathijs P Hendriks, Baukje Flameling, Lenneke Stabel, Madelief van de Ree, Jelmer Gietema, Winette T A van der Graaf, Olga Husson","doi":"10.1136/jmg-2025-111368","DOIUrl":"https://doi.org/10.1136/jmg-2025-111368","url":null,"abstract":"<p><strong>Purpose: </strong>Tumour genomic profiling, including whole genome sequencing (WGS), offers opportunities for refined diagnosis and personalised treatment for adolescents and young adults (AYAs) with advanced or poor prognostic cancer. This study explores AYAs' attitudes towards receiving WGS in standard oncological care, their preferences for the communication of results and the perceived impact of these results.</p><p><strong>Methods: </strong>Semistructured interviews were conducted with AYAs (aged 18-39 years at initial cancer diagnosis). Interviews were transcribed and analysed thematically using an inductive approach in NVivo (V.12).</p><p><strong>Results: </strong>16 AYAs participated. Analysis revealed five themes: (1) confidence in the current WGS procedure; (2) challenges in understanding and communicating purpose and results of WGS; (3) dual emotional impact of WGS results; (4) high value placed on hereditary information for self and loved ones and (5) balancing altruism and personal risk in genomic data sharing.</p><p><strong>Conclusion: </strong>AYAs with advanced cancer generally value WGS, even when results have no immediate clinical consequences. They describe benefits such as hope, reassurance and the opportunity to help future patients. However, misunderstandings about its purpose, difficulties in interpreting genomic findings and limited awareness of potential hereditary implications may limit its optimal use. Strengthening communication with age-appropriate, accessible explanatory materials will be essential to ensure AYAs understand the purpose and potential outcomes of WGS and can fully benefit from its implementation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147529829","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":"Colonoscopy surveillance in Lynch syndrome: what it prevents and what it does not.","authors":"Richard S Houlston, Malcolm G Dunlop","doi":"10.1136/jmg-2025-111311","DOIUrl":"10.1136/jmg-2025-111311","url":null,"abstract":"<p><p>Lynch syndrome (LS), synonymous with hereditary non-polyposis colorectal cancer (HNPCC), is caused by germline pathogenic variants in <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i> or <i>PMS2</i>, which confer an elevated lifetime risk of colorectal cancer (CRC). Since the early 2000s, colonoscopic surveillance has been recommended to reduce CRC incidence via polypectomy and mortality via early detection, with intervals now being tailored by gene. Early non-randomised studies suggested that surveillance imparted reductions in both CRC incidence and mortality. However, more recent prospective registry data, including the Prospective Lynch Syndrome Database (PLSD), consistently report high CRC incidence, despite regular colonoscopy. Nevertheless, mortality from CRC is low in individuals under surveillance, indicative of a beneficial effect of early cancer detection, likely through detection at a less advanced tumour stage. The apparent discrepancies between historical and recent studies regarding incidence reduction may reflect methodological issues (selection, confounding, overdiagnosis, immortal-time bias). However, LS tumourigenesis often follows an accelerated or alternative pathway (DNA mismatch repair (MMR)-deficient adenomas and MMR-deficient crypt foci) that may bypass conventional, easily detected precursor lesions. This may limit the impact of surveillance on incidence but preserve the mortality benefit through earlier-stage detection. Adherence, procedure quality and surveillance interval further influence outcomes. When weighting the evidence, large prospective consortium studies do not provide evidence in support of a substantial reduction in CRC incidence with 1-2 yearly surveillance for carriers of pathogenic <i>MLH1/MSH2</i> variants over longer intervals. However, smaller retrospective studies have suggested potential benefits. Less intensive schedules appear appropriate for carriers of pathogenic <i>PMS2</i> variants due to their low penetrance and more conventional adenoma-carcinoma pathways. In short, the evidence is strong that colonoscopic surveillance in LS reliably reduces CRC mortality but incompletely prevents incidence, especially in carriers with pathogenic variants whose cancers arise through an accelerated pathway and without a visible precursor. Improving adherence and endoscopic quality, considering adjunctive techniques (eg, faecal immunochemical testing between surveillance intervals, chromoendoscopy/AI (artificial intelligence) assistance), and exploring complementary strategies (eg, aspirin chemoprevention, biomarker-guided risk) are priorities. This narrative review synthesises current evidence, highlighting the need for robust future studies to optimise patient surveillance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147457556","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":"Comprehensive genotype-phenotype correlation analysis in 11 509 neonates carrying common deafness-associated pathogenic variants.","authors":"Jianjun Li, Zijun Zhan, Xiao Zhang, Bo Wu, Wenlan Liu","doi":"10.1136/jmg-2025-111135","DOIUrl":"https://doi.org/10.1136/jmg-2025-111135","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to analyse the distribution and genotype-phenotype correlations of pathogenic variants among 11 509 newborns carrying at least one common deafness-associated variant.</p><p><strong>Methods: </strong>A genotype distribution analysis was performed on 11 509 neonates identified as carriers of ≥1 pathogenic variant across four common deafness genes (<i>GJB2</i>, <i>SLC26A4</i>, <i>MT-RNR1</i> and <i>GJB3</i>) at our centre between January 2022 and December 2024. Hearing outcomes were assessed through a comprehensive evaluation protocol, initial screening (>48 hour after birth, before discharge), re-screening at 42 days and diagnostic evaluation by 3 months. Sanger sequencing identified potential compound heterozygous variants, and genotype-phenotype analysis was performed on infants with hearing loss (HL).</p><p><strong>Results: </strong>Among the 11 509 newborns carrying ≥1 pathogenic variant, two high-risk groups were identified: 653 newborns (5.67%) carrying biallelic pathogenic variants in <i>GJB2</i> and 113 newborns (0.98%) carrying the <i>MT-RNR1</i> m.1555A>G or m.1494C>T variants. However, only 58 infants were confirmed with HL, and 15.52% of these passed the initial hearing screening. Sanger sequencing reclassified 23.08% of presumed heterozygotes with HL as compound heterozygotes. Acoustic diagnostic results showed that <i>GJB2</i> c.235del homozygotes exhibited higher HL incidence (50% vs 6.51%) and more severe/profound HL (66.67% vs 7.14%) than <i>GJB2</i> c.109G>A homozygotes.</p><p><strong>Conclusions: </strong>Our data demonstrated that while genetic screening readily identifies infants with hereditary deafness susceptibility, newborn hearing screening fails to detect most of these high-risk cases due to the absence or delayed onset of HL. This gap obligates long-term audiological monitoring and highlights genetic testing's critical role in enabling early surveillance for later-onset HL.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512786","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 description of a large French series of individuals with Potocki-Lupski syndrome.","authors":"Alicia Coudert, Pauline Le Tanno, William Dufour, Patrick Edery, Aurelia Jacquette, Geoffroy Delplancq, Pascale Chambon, Chantal Missirian, Roseline Caumes, Laurence Faivre, Patrick Callier, Anne-Laure Mosca, Nathalie Marle, David Geneviève, Didier Lacombe, Céline Pebrel-Richard, Sylvia Redon, Renaud Touraine, Melanie Fradin, Sylvie Odent, Laurent Pasquier, Agnès Guichet, Sandra Mercier, Mathilde Nizon, Bertrand Isidor, Marie Vincent, Xavier Maximin Le Guillou Horn, Matthieu Egloff, Elise Schaefer, Anne-Marie Guerrot, Lyse Ruaud, Nicole Chemaly, Gwenaël Nadeau, Charles Coutton, Klaus Dieterich","doi":"10.1136/jmg-2025-111028","DOIUrl":"10.1136/jmg-2025-111028","url":null,"abstract":"<p><strong>Background: </strong>Potocki-Lupski syndrome (PTLS) is a rare genetic disorder, with an estimated prevalence of 1:25 000. Detection of a duplication at position 17p11.2 comprising the <i>RAI1</i> gene establishes the diagnosis. Deletion of this same region is responsible for Smith-Magenis syndrome (SMS). Hitherto, the non-specific clinical features included psychomotor and growth retardation and multiple congenital anomalies. Our aim was to further delineate the clinical spectrum of PLTS.</p><p><strong>Methods: </strong>We gathered a series of 56 individuals carrying a 17p11.2 duplication, one of the largest reported to date. We collected detailed phenotypic data and established a phenotypic comparison with individuals already described in the literature.</p><p><strong>Results: </strong>We corroborated the main clinical signs associated with PTLS and highlighted additional features present in a significant proportion in our series, such as intrauterine growth retardation or low birth weight, musculoskeletal and ophthalmological anomalies, and abnormalities of the skin appendages. In line with previous reports, behavioural disorders were frequently identified (23%). Yet unexpectedly, self-aggressive and hetero-aggressive behaviours, characteristic features of SMS, were found in a small number of individuals. Forty-six individuals harboured the recurrent duplication (85%), five had larger duplications (9%) and three had smaller duplications (6%). We did not identify inherited duplications when parental information was available (n=43).</p><p><strong>Conclusion: </strong>Our study refined the clinical features of PTLS and their relative frequencies. Our findings therefore contribute to improving management of people with PTLS. These open up new pathophysiological hypotheses involving <i>RAI1</i> gene dosage of the genesis and control of behaviour, as well as new, more complex regulatory pathways.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283915","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}