Journal of Medical Genetics最新文献

{"title":"'Knowing and Treating Kosaki/Penttinen syndrome' international collaborative consortium: recommendations for follow-up, natural history and a real-life observational study about safety and efficacy profile of tyrosine kinase inhibitors.","authors":"Yordi-Michaël Bouhatous, Cecilie Bredrup, Agnes Maurer, Liubinka Mirakovska, Alison Foster, Kenjiro Kosaki, Céline Jost, Jean-Baptiste Demoulin, Maxime Luu, Pierre Vabres, Jean-Emmanuel Kurtz, Elise Schaefer, Anne Guimier, Valerie Cormier-Daire, Derek Lim, Sarah Thompson, Lorin Olson, Hae Ryong Kwon, Cristina Aguirre-Rodriguez, Unai Hernandez-Dorronsoro, Itziar Martinez-Soroa, Helena Iznardo, José-Manuel Mascaró, Eulalia Baselga, Silvia Kalantari, Alessandro Mussa, Andrea Gazzin, Diana Carli, Ingrid Svinvik, Hatice Mutlu-Albayrak, Sarah Bluefeather, Yuri Zarate, Toshiki Takenouchi, Thirona Naicker, Antoinette Chateau, Ashmika Gokhul, Anele Dube-Pule, Muzhirah Haniffa, Winnie Ong Peitee, Ann Nordgren, Maud Carpentier, Christine Binquet, Anne-Sophie Briffaut, Laurence Bal, Dinel Pond, Cecilie F Rustad, Marc Bardou, Laurence Faivre","doi":"10.1136/jmg-2024-110600","DOIUrl":"10.1136/jmg-2024-110600","url":null,"abstract":"<p><strong>Background: </strong>5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in <i>PDGFRB</i>. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes.</p><p><strong>Material and methods: </strong>The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place.</p><p><strong>Results: </strong>As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use.</p><p><strong>Conclusion: </strong>The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"656-663"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707736","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":"609-616"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","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}

{"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":"617-623"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","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":"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":"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":"624-627"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505049/pdf/","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":"OA","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":"10.1136/jmg-2025-110710","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"628-630"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505085/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on <i>UBTF</i> haploinsufficiency associated with <i>UBTF</i>-related global developmental delay and distinctive facial features without neuroregression.","authors":"Tony Yammine, Sandra Mercier, Céline Poirsier, Nathalie Bednarek, Christine Clavel, Benjamin Cogné, Jan M Friedman, Sila Rogan, Marlène Rio, Laurence Lodé, Alban Ziegler","doi":"10.1136/jmg-2025-110686","DOIUrl":"10.1136/jmg-2025-110686","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"653-655"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608588","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":"Biallelic pathogenic <i>TULP3</i> variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations.","authors":"Jia-Qi Li, Yan Li, Ruida He, Zaisheng Lin, Jiayan Feng, Bin Yang, Qing-Wen Shan, Sixing Chen, Ye Cheng, Qinghe Xing, Muqing Cao, Jian-She Wang","doi":"10.1136/jmg-2025-110658","DOIUrl":"10.1136/jmg-2025-110658","url":null,"abstract":"<p><strong>Background: </strong>Biallelic pathogenic <i>TULP3</i> variants have been associated with a novel ciliopathy named hepatorenocardiac degenerative fibrosis, which is characterised by hepatic fibrosis in childhood or early adulthood, fibrocystic kidney disease later in life and hypertrophic cardiomyopathy in the elderly. Its genotype and phenotype spectrum are largely unknown.</p><p><strong>Methods: </strong>Patients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of <i>TULP3</i> were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.</p><p><strong>Results: </strong>Two unrelated children carrying biallelic rare variants in <i>TULP3</i> were identified. Patient 1 had variants c.666T>G, p. (Tyr222Ter) and c.1291G>C, p. (Gly431Arg). She initially presented with neonatal cholestasis, which rapidly progressed to liver fibrosis, with liver transplantation at 2 years of age. She also had intellectual disability and attention deficit hyperactivity disorder. Patient 2 had variants c.73C>T, p. (Gln25Ter) and c.1211T>G, p. (Met404Arg). He was found to have liver fibrosis, portal hypertension and abnormal cranial imaging at the age of 7.5 years. Both non-sense variants, c.73C>T and c.666T>G, were predicted to result in non-sense-mediated mRNA decay. Missense variant Met404Arg abolished TULP3 expression, while Gly431Arg reduced the localisation of TULP3 in cilia. Both Met404Arg and Gly431Arg impaired ciliogenesis and the trafficking of ARL13B and INPP5E into cilia.</p><p><strong>Conclusion: </strong>Severe neonatal cholestasis and/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous <i>TULP3</i> variants. Missense variants in <i>TULP3</i> may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"631-640"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511994","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":"A novel 8-octapeptide repeat insertion in <i>PRNP</i> causing Huntington disease-like 1 in a Chinese family: a case report and literature review.","authors":"Jie Ni, Fangxue Zheng, Lihua Yu, Fangping He, Fang Ji, Yi Ling, Ping Liu, Guoping Peng, Qing Ke","doi":"10.1136/jmg-2024-110520","DOIUrl":"10.1136/jmg-2024-110520","url":null,"abstract":"<p><strong>Background: </strong>Approximately 1-3% of patients with Huntington disease (HD) present with HD-like phenotype but test negative for the HD gene, suggesting other causes.</p><p><strong>Methods: </strong>This study presents the first case of Huntington disease-like 1 (HDL-1) in a Chinese family and summarises the clinical features of previously reported HDL-1 cases and patients with octapeptide repeat insertion (OPRI) mutations.</p><p><strong>Results: </strong>The proband, a 36-year-old woman, presented with progressive involuntary movements, bradykinesia, cognitive decline and personality changes over 6 years, worsening over the past year. Similar manifestations were noted in her grandmother, father and aunt. Genetic testing revealed an 8-OPRI mutation in <i>PRNP</i>, confirming HDL-1. Neuroimaging showed increased T2-Fluid Attenuated Inversion Recovery (FLAIR) signals in the hippocampi and atrophic changes in the frontal and parietal lobes. Electroencephalography indicated a slowed background rhythm. A 1-year follow-up visit showed amelioration of choreic movements. A literature review identified five families with HDL-1, with age of onset ranging from 18 years to 54 years and disease duration from 3 months to over 20 years. Common manifestations included movement disorders, dementia, personality changes and heterogeneous symptoms such as epilepsy. Imaging showed ventricular enlargement and diffuse brain atrophy, primarily affecting the basal ganglia, frontal lobes, temporal lobes and cerebellum. Pathologically, prion protein antibody staining was positive, although spongiform changes were not prominent.</p><p><strong>Conclusion: </strong>These cases highlight the importance of considering familial prion diseases in patients with hereditary chorea and a negative HD gene test. Careful attention to treatment and follow-up can provide valuable insights for managing these patients.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"647-652"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216085","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":"New variants and genotype-phenotype correlation in <i>KIF5A</i> mutation: the contribution of a large Italian cohort.","authors":"Rosangela Ferese, Antonio Suppa, Rosa Campopiano, Simona Scala, Federica Sammarone, Luana Di Pilla, Alba Di Pardo, Maria Antonietta Chiaravalloti, Anna Maria Griguoli, Milena Cannella, Carmelo D'Alessio, Marianna Storto, Mirco Fanelli, Alessandro Zampogna, Martina Patera, Maurizio Inghilleri, Marco Ceccanti, Chiara Cambieri, Fabio Buttari, Cristina Peconi, Emiliano Giardina, Stefania Zampatti, Diego Centonze, Stefano Gambardella","doi":"10.1136/jmg-2025-110801","DOIUrl":"10.1136/jmg-2025-110801","url":null,"abstract":"<p><strong>Background: </strong>Variants in the Kinesin-family member 5A (<i>KIF5A)</i> gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of <i>KIF5A</i> variants and their genotype-phenotype correlation.</p><p><strong>Methods: </strong>390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome.</p><p><strong>Results: </strong>Five patients have been found to carry causative variants in the <i>KIF5A</i> gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease.</p><p><strong>Conclusion: </strong>These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"641-646"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497350","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":"Comprehensive genetic landscapes and clinical heterogeneity in nanophthalmos: new insights from a large Chinese cohort.","authors":"Qingdan Xu, Yiwen Zhou, Jiajian Wang, Xiangmei Kong, Junyi Chen, Yi Dai, Shaohong Qian, Xiaobo Yu, Xinghuai Sun, Yuhong Chen","doi":"10.1136/jmg-2025-110905","DOIUrl":"https://doi.org/10.1136/jmg-2025-110905","url":null,"abstract":"<p><strong>Background: </strong>Nanophthalmos is a rare ocular condition characterised by a significantly short axial length (AL) and high hyperopia, often associated with various complications. This study aims to provide a comprehensive analysis of the clinical and genetic features of nanophthalmos in a large Chinese cohort.</p><p><strong>Methods: </strong>A total of 105 patients from unrelated families diagnosed with nanophthalmos were included. Genetic testing was performed using whole exome sequencing to identify variants in genes associated with the condition. Clinical features, including demographic data, the presence of accompanying clinical findings and various ocular parameters, were compared across different genetic groups.</p><p><strong>Results: </strong>Whole exome sequencing revealed variants in four key genes: <i>PRSS56</i>, <i>MFRP</i>, <i>MYRF</i> and <i>TMEM98</i>, with a detection rate of 71.43%. Autosomal recessive genes (<i>PRSS56</i> and <i>MFRP</i>) were associated with shorter AL, higher hyperopia, shallower vitreous chamber depth and steeper corneal curvatures (larger K1 and K2). In contrast, autosomal dominant genes (<i>MYRF</i> and <i>TMEM98</i>) were linked to earlier onset of glaucoma and a higher incidence of multiple ciliary body cysts. In the patients carrying variants in <i>PRSS56</i> and <i>MFRP</i>, biallelic variants were associated with more severe phenotypes, including more extreme ocular parameters and increased risks of specific complications, compared with monoallelic variants.</p><p><strong>Conclusion: </strong>This study represents the largest cohort of nanophthalmos patients reported to date, expanding the genetic and clinical understanding of the condition. It identifies novel variants and provides valuable insights into genotype-phenotype correlations, highlighting the impact of genetic variation on the disease severity and associated complications of nanophthalmos.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092189","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}