Journal of Medical Genetics最新文献

{"title":"Evaluation of whole-body MRI for cancer early detection in Li-Fraumeni syndrome.","authors":"Peter Sodde, Zerin Hyder, Sarah Pugh, Fiona Lalloo, Richard Martin, Calvin Soh, Jawad Naqvi, Richard Whitehouse, D Gareth Evans, Emma Roisin Woodward","doi":"10.1136/jmg-2025-110704","DOIUrl":"https://doi.org/10.1136/jmg-2025-110704","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is a high-risk hereditary cancer predisposition syndrome affecting 1 in 5000 individuals. Current standard of care in adults includes annual whole-body MRI (WB-MRI) and MRI brain (MRB) surveillance to enable early cancer detection. We performed a retrospective single-centre study of adults with <i>TP53</i> pathogenic germline variants or proven somatic mosaicism undergoing annual WB-MRI surveillance between January 2012 and January 2024, and MRB surveillance between August 2017 and January 2024. 325 WB-MRI scans were performed in 75 individuals. 17 cancers were diagnosed in 16 individuals. Nine out of 17 cancers were WB-MRI detected (7/9 had stage 1/2 disease). Benign incidental findings were identified in 89/325 (27.4%) of WB-MRI scans, prompting 53 additional investigations. As a stand-alone surveillance tool, WB-MRI demonstrated a pan-cohort specificity of 95.5%, negative predictive value of 97.4% and sensitivity of 42.9%. 32 individuals underwent 53 MRB scans detecting one cancer. We report the findings from the longest and largest single-centre experience of WB-MRI surveillance for cancer early detection in adults with LFS, demonstrating a high and acceptable level of cancer exclusion but modest sensitivity with WB-MRI prompting a significant number of additional investigations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528356","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":"Investigating the use of a patient-facing digital app to support Lynch syndrome carriers in the management of their condition.","authors":"Megan I Hopkinson, Reena Sooch, Charlotte Beauvais, Shirley V Hodgson, Tracy Ann Smith, Madonna Jonhera, Stan Shepherd, Julian Barwell","doi":"10.1136/jmg-2025-110710","DOIUrl":"https://doi.org/10.1136/jmg-2025-110710","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505986","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 DNA and RNA sequencing for inherited polyposis and colorectal cancer: cryptic intronic variants and multiple mutational mechanisms.","authors":"Angela L Jacobson, Amal AbuRayyan, Suleyman Gulsuner, Haley Slater, Yagiz Anasiz, Sirajummuneer M Ahmad, Ming K Lee, Jessica Mandell, Emily J Rettner, Eric Q Konnick, Colin Pritchard, Mary-Claire King, Tom Walsh, Brian H Shirts","doi":"10.1136/jmg-2025-110851","DOIUrl":"10.1136/jmg-2025-110851","url":null,"abstract":"<p><strong>Background: </strong>Molecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps.</p><p><strong>Methods: </strong>Adaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results.</p><p><strong>Results: </strong>Genetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into <i>MSH2</i> of an Alu element, leading to extension of transcription into the affected intron and a stop. Patient 2 was heterozygous for deep intronic insertion into <i>APC</i> of a Long Interspersed Nuclear Element (LINE), creating a pseudoexon and a stop. Patient 3 was compound heterozygous at <i>MLH3</i>, including a cryptic intronic substitution leading to exon skipping and a stop. Patient 4 was compound heterozygous at <i>MUTYH</i>, including a deep intronic deletion yielding an extremely short intron and transcriptional loss of an exon encoding a critical protein domain.</p><p><strong>Conclusion: </strong>Paired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505987","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":"Economic evaluation of personalised versus conventional risk assessment for women who have undergone testing for hereditary breast and ovarian cancer genes: a modelling study.","authors":"Qin Xi, Nichola Fennell, Stephanie Archer, Marc Tischkowitz, Antonis C Antoniou, Stephen Morris","doi":"10.1136/jmg-2024-109948","DOIUrl":"10.1136/jmg-2024-109948","url":null,"abstract":"<p><strong>Background: </strong>The management of women with germline pathogenic variants (GPVs) in breast (BC) and ovarian cancer (OC) susceptibility genes is focused on surveillance and risk-reducing surgery/medication. Most women are assigned an average range of risk and treated accordingly, but it is possible to personalise this. Here, we explore the economic impact of risk personalisation.</p><p><strong>Method: </strong>We compared two strategies for risk stratification for female participants: conventional risk assessment (CRA), which only involves information from genetic testing and personalised risk assessment (PRA), using genetic and non-genetic risk modifiers. Three different versions of PRA were compared, which were combinations of polygenic risk score and questionnaire-based factors. A patient-level Markov model was designed to estimate the overall National Health Service cost and quality-adjusted life years (QALYs) after risk assessment. Results were given for 20 different groups of women based on their GPV status and family history.</p><p><strong>Results: </strong>Across the 20 scenarios, the results showed that PRA was cost-effective compared with CRA using a £20 000 per QALY threshold in women with a GPV in <i>PALB2</i> who have OC or BC+OC family history, and women with a GPV in <i>ATM</i>, <i>CHEK2</i>, <i>RAD51C</i> or <i>RAD51D</i>. For women with a GPV in <i>BRCA1</i> or <i>BRCA2</i>, women with no pathogenic variant and women with a GPV in <i>PALB2</i> who have unknown family history or BC family history, CRA was more cost-effective. PRA was cost-effective compared with CRA in specific situations predominantly associated with moderate-risk BC GPVs (<i>RAD51C</i>/<i>RAD51D</i>/<i>CHEK2</i>/<i>ATM</i>), while CRA was cost-effective compared with PRA predominantly with high-risk BC GPVs (<i>BRCA1</i>/<i>BRCA2</i>/<i>PALB2</i>).</p><p><strong>Conclusion: </strong>PRA was cost-effective in specific situations compared with CRA in the UK for assessment of women with or without GPVs in BC and OC susceptibility genes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"450-456"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006961","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":"Effects of higher-than-expected control population allele frequency on classification of loss-of-function variants in cancer susceptibility genes.","authors":"Miriam J Smith, George J Burghel, D Gareth Evans","doi":"10.1136/jmg-2025-110703","DOIUrl":"10.1136/jmg-2025-110703","url":null,"abstract":"<p><p>A query was sent to the cancer predisposition gene variant database Cancer Variant Interpretation Group UK, on the nonsense variant in NM_032043.3(<i>BRIP1</i>):c.2392C>T,p.(Arg798Ter). The submitter classified this as a variant of uncertain significance, providing very strong variant effect evidence with the intention of adding supporting pedigree information, according to the guidelines used for classification. However, the relatively high population frequency in the UKB cohort of 367/439 920 (0.083%) was a concern as it is higher than expected for the disease frequency, which would reduce the predicted pathogenicity score. This situation highlights the increasing concerns over the use of population data in pathogenicity classification of truncating/loss-of-function (LoF) variants in known cancer predisposition genes, particularly since the addition of UKB control data. Here, we have conducted a series of case-control comparisons for common truncating variants in known breast/ovarian cancer-associated genes, as well as <i>LZTR1</i>-related schwannomatosis, to address this issue using our Manchester cancer screening population compared with controls in UKB data.Our data show strong ORs for these common truncating variants. We propose that for truncating variants in cancer susceptibility genes with a significant case-control OR, apparently conflicting population frequency evidence criteria should be avoided.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"464-466"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029917","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>LSM1</i> c.231+4A>C hotspot variant is associated with a novel neurodevelopmental syndrome: first patient cohort.","authors":"Sivan Reytan Miron, Alina Kurolap, Bassam Abu-Libdeh, Abdel Salam Abu-Libdeh, Clara Velmans, Florian Erger, Vera Riehmer, Tzung-Chien Hsieh, Hellen Lesmann, Adi Reches, Chofit Chai Gadot, Adi Mory, Motee Al-Ashhab, Christian Netzer, Nadirah Damseh, Hagit Baris Feldman","doi":"10.1136/jmg-2024-110574","DOIUrl":"10.1136/jmg-2024-110574","url":null,"abstract":"<p><strong>Background: </strong>The <i>LSM1</i> gene encodes a subunit of the conserved LSM1-7 protein complex involved in messenger RNA (mRNA) metabolism. Variants in the <i>LSM1</i> gene have been described in two separate case reports. The first published report identified the homozygous splice-site variant c.231+4A>C, while the second reported a homozygous missense variant. Nevertheless, variation in <i>LSM1</i> has yet to be established as disease-causing in humans.</p><p><strong>Methods: </strong>Through exome sequencing and detailed phenotyping, we report six syndromic paediatric patients with the homozygous c.231+4A>C variant in the <i>LSM1</i> gene, collected via GeneMatcher. GestaltMatcher was used to analyse facial feature similarity, and real-time quantitative PCR (RT-qPCR) confirmed the splice defect caused by the variant. Haplotype analysis assessed whether this variant resulted from independent occurrences or a common ancestral haplotype.</p><p><strong>Results: </strong>Patients presented with dysmorphic facial features, developmental delay and multisystemic involvement, including urological, cardiac and skeletal manifestations, showcasing the phenotypic spectrum of this syndrome. RT-qPCR confirmed that the c.231+4A>C variant causes exon 3 skipping, producing negligible <i>wild-type LSM1</i> mRNA expression. Elevated mutant isoform expression confirmed pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We identified this variant in the Muslim Arab and Ashkenazi Jewish populations and determined that it represents a hotspot variant through haplotype analysis.</p><p><strong>Conclusion: </strong>Our findings establish <i>LSM1</i>, and specifically the c.231+4A>C homozygous variant, as causative for a novel autosomal recessive syndromic neurodevelopmental disorder. These results expand the understanding of <i>LSM1</i>-related diseases and provide a foundation for further investigation of its molecular mechanisms.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"441-449"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015469","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":"Rare missense variants in <i>FNDC1</i> are associated with severe adolescent idiopathic scoliosis.","authors":"Wu-Lin Charng, Gabe Haller, Julia Whittle, Momchil Nikolov, Addison Avery, Jose Morcuende, Philip Giampietro, Cathy Raggio, Nancy Miller, Anne E Justice, Natasha T Strande, Mark Seeley, Dale L Bodian, Carol A Wise, Diane S Sepich, Matthew B Dobbs, Christina A Gurnett","doi":"10.1136/jmg-2024-110586","DOIUrl":"10.1136/jmg-2024-110586","url":null,"abstract":"<p><strong>Background: </strong>Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.</p><p><strong>Methods: </strong>To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. <i>FNDC1</i> function was investigated in <i>fndc1</i> null mutant zebrafish.</p><p><strong>Results: </strong>Rare variants were enriched in 84 genes, including <i>RAF1</i> (Noonan syndrome), <i>FBN1</i> (Marfan syndrome) and <i>FNDC1,</i> in individuals with severe AIS. <i>FNDC1</i>, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). <i>FNDC1</i> variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, <i>FNDC1</i> rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the <i>fndc1</i> locus in zebrafish resulted in increased bone mineral density.</p><p><strong>Conclusion: </strong>We broadened the phenotype associated with <i>RAF1</i> and <i>FBN1</i> variants and identified <i>FNDC1</i> as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of <i>FNDC1</i> missense variants with AIS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"427-435"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015097","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":"Electronic health record-based registry for identification of individuals at risk for hereditary cancer syndromes.","authors":"Vinit Singh, Thomas E Rafter, Mohamad Sharbatji, Jing Liu, Quiana Brown, Karina Brierley, Claire Healy, Rosa M Xicola, Nitu M Kashyap, Xavier Llor","doi":"10.1136/jmg-2025-110718","DOIUrl":"10.1136/jmg-2025-110718","url":null,"abstract":"<p><strong>Background: </strong>Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis.</p><p><strong>Methods: </strong>National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of 'at-risk'. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients.</p><p><strong>Results: </strong>Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001).</p><p><strong>Conclusions: </strong>This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"457-463"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996437","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":"Short stature, brachydactyly and joint contractures associated with novel <i>FBN2</i> variants in two families.","authors":"Petra Loid, Fan Wang, Otto Lennartsson, Mari Muurinen, Alice Costantini, Sakshi Vats, Maria Lodefalk, Ola Nilsson, Outi Mäkitie","doi":"10.1136/jmg-2024-110533","DOIUrl":"10.1136/jmg-2024-110533","url":null,"abstract":"<p><strong>Background: </strong>Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by <i>FBN2</i>, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.</p><p><strong>Methods and results: </strong>We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the <i>FBN2</i> gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The <i>FBN2</i> deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.</p><p><strong>Conclusion: </strong>Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of <i>FBN2-</i>related phenotypes. The study supports the role of <i>FBN2</i> variants in growth failure and expands the molecular spectrum of <i>FBN2</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"436-440"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811499","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":"Reproductive decision-making and pregnancy in germline <i>CDH1</i> variant carriers.","authors":"Amber Famiglietti Gallanis, Cassidy Bowden, Rachael Lopez, Jessica Turner, Grace-Ann Fasaye, Shruthi Reddy Perati, Jonathan M Hernandez, Andrew Blakely, Jeremy L Davis","doi":"10.1136/jmg-2025-110857","DOIUrl":"10.1136/jmg-2025-110857","url":null,"abstract":"<p><strong>Background: </strong>Diagnosis of a hereditary cancer syndrome may impact family planning, particularly in reproductive age individuals. Factors influencing reproductive decision-making are understudied in individuals with germline <i>CDH1</i> pathogenic or likely pathogenic (P/LP) variants.</p><p><strong>Methods: </strong>We characterised reproductive decision-making and perinatal outcomes in 121 individuals aged 18-49 with hereditary diffuse gastric and lobular breast cancer syndrome due to a germline <i>CDH1</i> P/LP variant.</p><p><strong>Results: </strong>Half of individuals (50%, 60/121) reported their <i>CDH1</i> diagnosis impacted family planning. Psychosocial and economic barriers to reproduction were encountered by 47% (56/119) of patients. Additionally, 12% (15/121) of individuals delayed pregnancy to prioritise personal cancer risk management with either endoscopic surveillance, prophylactic total gastrectomy (PTG) or mastectomy. Women were more likely to experience guilt about passing their <i>CDH1</i> variant to offspring compared with men. Perinatal and fetal outcomes were investigated in six women who gave birth at a median time of 24 months (IQR 20-44) after PTG. Maternal micronutrient deficiencies were not uncommon in pregnant women after PTG despite compliance with a bariatric, prenatal multivitamin. Majority of women who became pregnant after PTG reported worsening post-gastrectomy syndromes. Most infants (90%, 9/10) born after PTG were full-term and no fetal complications were reported.</p><p><strong>Conclusion: </strong>Reproductive decision-making is complex in individuals with germline <i>CDH1</i> variants, who often encounter psychosocial and physical challenges during family planning and pregnancy. However, successful pregnancy is possible after PTG with the guidance of a multidisciplinary team including maternal fetal medicine specialists and a registered dietitian.</p><p><strong>Trial registration number: </strong>NCT03030404.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336689","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}