Journal of Medical Genetics最新文献

{"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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","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":"Reclassification of candidate splicing variants refines clinically conflicting interpretations in <i>SLC26A4</i>-associated hearing loss.","authors":"Yue Liang, Shubin Fang, Xiaoqing Cen, Yueying Wang, Anhai Chen, Lusha Huang, Juan Wang, Wenbin Lei, Guanxia Xiong, Kaitian Chen","doi":"10.1136/jmg-2024-110425","DOIUrl":"https://doi.org/10.1136/jmg-2024-110425","url":null,"abstract":"<p><strong>Purpose: </strong>Variants in the human <i>SLC26A4</i> gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.</p><p><strong>Methods: </strong>In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of <i>SLC26A4</i> gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.</p><p><strong>Results: </strong>In a cohort of 178 patients carrying <i>SLC26A4</i> variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent <i>SLC26A4</i> gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14/323) of the variants within our cohort.</p><p><strong>Conclusion: </strong>By using the standard classification of <i>SLC26A4</i> variants, our results were able to interpret novel or uncertain <i>SLC26A4</i> gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying <i>SLC26A4</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012014","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":"Novel biallelic <i>NUP107</i> variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations.","authors":"Loisa Dana Bonde, Laura Hecher, Malik Alawi, Kirsten P Forbes, Joseph D Symonds, Mark J Hamilton, Kerstin Kutsche","doi":"10.1136/jmg-2025-110671","DOIUrl":"https://doi.org/10.1136/jmg-2025-110671","url":null,"abstract":"<p><p>Biallelic variants in <i>NUP107</i> cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with syndromic SRNS have microcephaly, developmental delay or intellectual disability and short stature. Simplified gyration is observed in some individuals. We report on a 2-year-old girl with novel biallelic <i>NUP107</i> variants, c.2606G>T; p.(Gly869Val) and c.1576+1G>A, proteinuria and a severe neurodevelopmental disorder with microcephaly, developmental delay, early-onset seizures, sensorineural hearing loss and brain structural anomalies, including simplified gyral pattern and hypoplasia of the corpus callosum, pons, brainstem and cerebellum. NUP107 is part of the NUP107-160 complex, which, together with other proteins termed nucleoporins, forms the nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport and other cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced <i>NUP107</i> mRNAs with a frameshift and premature stop codon leading to non-sense-mediated mRNA decay, reduced levels of <i>NUP107</i> transcripts, reduced NUP107 and NUP133 proteins, and a reduced NPC number. In addition, an abnormal nucleolar morphology was found in patient-derived cells. Our functional data support the conclusion that the <i>NUP107</i> variants underlie the patient's phenotype, thereby broadening the clinical spectrum associated with <i>NUP107</i> variants to include abnormal brain development.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996441","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":"UK clinical practice guidelines for the management of patients with constitutional <i>POT1</i> pathogenic variants.","authors":"Olga Tsoulaki, D Gareth Evans, Khushboo Sinha, Neil Rajan, Farah Bakr, Helen Hatcher, Andrea Napolitano, Elena Finn, Sunil Iyengar, Aslam Sohaib, Timothy J Sadler, Claire Forde, Emma Roisin Woodward, Terri P McVeigh, Marc Tischkowitz, Fiona Lalloo, Helen Hanson","doi":"10.1136/jmg-2025-110638","DOIUrl":"https://doi.org/10.1136/jmg-2025-110638","url":null,"abstract":"<p><p>Constitutional or germline pathogenic variants (GPVs) in <i>protection of telomeres 1 (POT1</i>) are associated with a variety of tumours resulting in the recognition of POT1-tumour predisposition syndrome (POT1-TPDS). These tumours may include cutaneous melanoma, angiosarcoma, haematological malignancy and brain tumours. Due to the rarity of <i>POT1</i> GPVs and limited available data, the overall lifetime cancer risks for individuals with POT1-TPDS are unclear. Furthermore, there is scant evidence to support the role of surveillance in early cancer detection in this patient group. A recent international publication suggested a surveillance protocol similar to that used in Li-Fraumeni Syndrome (LFS) could be offered to <i>POT1</i> pathogenic variant carriers, particularly where there are LFS-like features. However, current evidence for POT1-TPDS is not supportive of an equivalent lifetime cancer risk. Given the inclusion of <i>POT1</i> in the National Test Directory in England and the need for UK-based guidance, an expert group undertook a literature review to assess the phenotypic spectrum of POT1-TPDS and to provide lifetime risk estimates of <i>POT1</i>-associated cancers. The available evidence was shared with a small working group of experts that included clinical geneticists, dermatologists, sarcoma specialists, haematologists and radiologists to cover all aspects of the cancers most commonly associated with POT1-TPDS. Following structured expert group discussions, we achieved consensus on best practice recommendations for a POT1-TPDS UK management protocol.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012016","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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic heterogeneity in <i>DYNC2H1</i>-related short-rib thoracic dysplasia: antenatal indicators and postnatal outcomes.","authors":"Nikhil Pattani, Nour Elkhateeb, Aakash Joshi, Juan Carlos Del Rey Jimenez, Joy L Barber, Pilar Palmrich, Helen Firth, Sarju G Mehta, Leila Amel Riazat Kesh, Jennifer Campbell, Jenny Carmichael, Sahar Mansour","doi":"10.1136/jmg-2024-110369","DOIUrl":"https://doi.org/10.1136/jmg-2024-110369","url":null,"abstract":"<p><strong>Introduction: </strong><i>DYNC2H1</i>-related short-rib thoracic dysplasia with/without polydactyly (SRTD), formerly asphyxiating thoracic dystrophy-Jeune syndrome, is a rare genetic skeletal disorder characterised by a narrow thorax, short ribs, shortened long bones and brachydactyly/polydactyly. <i>DYNC2H1</i>-related SRTD shows significant phenotypic variability. There is limited information regarding correlations between genotypes, antenatal ultrasound findings and clinical phenotypes and severity.</p><p><strong>Methods: </strong>A retrospective study of confirmed <i>DYNC2H1</i>-related SRTD cases was conducted through paper and digital medical records. Data collected included patient demographics, initial presentation, postnatal progression, childhood follow-up, antenatal ultrasound imaging, postnatal skeletal surveys and genetic variant analysis.</p><p><strong>Results: </strong>Nine individuals from eight families across three tertiary genetic centres in England were included in the study. Eight presented in the antenatal period (gestation 14-36 weeks) and one in the postnatal period at 6 weeks. All nine displayed a narrow thorax and eight displayed shortened long bones (humerus and/or femur). Polydactyly was less common and seen in only four individuals. Phenotypic severity was variable, including mild (n=4), moderate requiring respiratory support (n=2) and severe/lethal (n=3) cases. Earlier antenatal presentation and more significant femur shortening and bowing were predictive of poor postnatal prognosis, and there were no clear genotype-phenotype correlations. We also report seven novel <i>DYNC2H1</i> variants, not previously reported.</p><p><strong>Conclusion: </strong><i>DYNC2H1</i>-related SRTD exhibits significant phenotypic variability which cannot be reliably predicted by genotype but has some correlation with time of gestational presentation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010606","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":"Outcomes and experiences of genetic testing in children with congenital heart disease.","authors":"Ansley M Morrish, Bridget R O'Malley, Desiree C K Hilton, Annabel E Webb, Bruce Bennetts, Gary F Sholler, Janine Smith, Gillian M Blue","doi":"10.1136/jmg-2024-110553","DOIUrl":"10.1136/jmg-2024-110553","url":null,"abstract":"<p><strong>Background: </strong>Following genomic advances, genetic testing options for paediatric patients with congenital heart disease (CHD) have evolved significantly. A single-site audit was conducted to assess testing outcomes and a survey created to explore family experiences and preferences.</p><p><strong>Method: </strong>All genetic tests ordered in postcardiac surgery patients with CHD at The Children's Hospital at Westmead between January 2017 and December 2021 were reviewed. Diagnostic yield, clinical and demographic factors, and testing trends over time were evaluated. Surveys were sent to parents of children who had met a clinical geneticist (n=112).</p><p><strong>Results: </strong>Genetic testing was completed in 607 individuals (74 molecular testing; 533 cytogenetic testing only). The diagnostic rate was 36% and 9%, respectively. Use of molecular testing significantly increased over time (p=0.033), but yield did not (p=0.288). Molecular testing yield was high in neonates (64%), and patients with extracardiac anomalies (40%) or relevant family history (40%). Brain (p=0.022), haematological/cancer (p≤0.001), immune (p≤0.001), endocrine (p≤0.001) anomalies and intellectual disability (p=0.027) were associated with a diagnosis following cytogenetic testing. Short stature was significantly associated with diagnostic yield following molecular testing (p=0.012). Survey respondents (n=28) reported a positive experience (p=0.013) with minimal decisional regret (p=0.322).</p><p><strong>Conclusion: </strong>Cytogenetic testing remains an important first-tier test in CHD. Furthermore, molecular testing guided by a clinical geneticist generates a high rate of genetic diagnoses. Parents of children with CHD value genetic testing with little regret.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"335-344"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515913","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":"Limitations of genomics to predict and treat autism: a disorder born in the womb.","authors":"Yehezkel Ben-Ari, Étienne É Danchin","doi":"10.1136/jmg-2024-110224","DOIUrl":"10.1136/jmg-2024-110224","url":null,"abstract":"<p><p>Brain development involves the sequential expression of vulnerable biological processes including cell proliferation, programmed cell death, neuronal migration, synapse and functional unit formation. All these processes involve gene and activity-dependent events that can be distorted by many extrinsic and intrinsic environmental factors, including stress, microbiota, inflammatory signals, hormonal signals and epigenetic factors, hence leading to disorders born in the womb that are manifested later in autism spectrum disorders (ASDs) and other neurodevelopmental disorders. Predicting and treating such disorders call for a conceptual framework that includes all aspects of developmental biology. Here, taking the high incidence of ASDs as an example, we first discuss the intrinsic limitations of the genetic approach, notably the widely used twin studies and SNPs. We then review the long list of in utero events that can deviate developmental sequences, leading to persistent aberrant activity generated by immature misplaced and misconnected neuronal ensembles that are the direct cause of ASD. In a clinical perspective, we suggest analysing non-genetic maternity data to enable an early prediction of babies who will develop ASD years later, thereby facilitating early psycho-educative techniques. Subsequently, agents capable of selectively silencing malformed immature networks offer promising therapeutic perspectives. In summary, understanding developmental processes is critical to predicting, understanding and treating ASD, as well as most other disorders that arise in the womb.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"303-310"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624997","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":"Canadian consensus for the assessment and testing of Lynch syndrome.","authors":"Melyssa Aronson, Laura Palma, Kara Semotiuk, Jennifer Nuk, Aaron Pollett, Harminder Singh, Heidi Rothenmund, Hilary Racher, Jaime Jessen, Stephen E Pautler, Alison Rusnak, Mari Rutka, Holly Etchegary, Teresa Tiano, Pardeep Kaurah, Lesa Dawson, Andrea Hawrysh, Thomas Ward, Angela Bedard, Brandon S Sheffield, Jordan Lerner-Ellis, Karine Jacob, Sarah Ferguson, Christina A Kim, Erin Chamberlain, Kimberly Dornan, Larissa Waldman, Spring Holter, Janice Horte, Angela Hyde, Janice Kwon, Andree MacMillan, Melanie O'Loughlin, Uri Tabori, Steven Gallinger, Raymond Kim","doi":"10.1136/jmg-2024-110465","DOIUrl":"10.1136/jmg-2024-110465","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome caused by a germline pathogenic variant, or epigenetic silencing, of a mismatch repair (MMR) gene, leading to a wide cancer spectrum with gene-specific penetrance. Ascertainment, assessment and testing of LS individuals is complex. A Canadian national guideline is needed to ensure equitable access to patient care across the country.</p><p><strong>Methods: </strong>The Canadian Lynch Syndrome (CDN-LS) working group was formed in 2021, consisting of 37 multidisciplinary LS experts and patient partners. To formulate consensus statements, a national environmental scan, Canadian clinical survey and literature review were undertaken. The e-Delphi method was used to reach consensus statements among the CDN-LS group.</p><p><strong>Results: </strong>The CDN-LS group voted on 21 statements, and 18 statements were adopted with over 80% agreement, including 16 statements that had over 90% agreement. These statements provide comprehensive guidelines on universal MMR reflex testing, cascade tumour testing (<i>MLH1</i> promoter methylation, <i>BRAF</i>, somatic MMR), germline testing, therapeutics and patient advocacy.</p><p><strong>Conclusion: </strong>This is the first comprehensive Canadian guideline for LS providing guidance to genetic specialists, laboratories, primary care providers and healthcare providers caring for patients with LS. It is endorsed by the Canadian College of Medical Genetics and the Canadian Association of Genetic Counsellors. The consensus statements are presented as a model for standard of care that improves equitable access to health services for LS across the country. Future work should include a national consensus on LS surveillance, with a goal to harmonise LS care across all provincial and territorial healthcare authorities.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"326-334"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624993","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":"Whole-exome sequencing reveals sex difference in the genetic architecture of high myopia.","authors":"Xingchen Liu, Jiacheng Liang, Shasha Li, Yuhe Yang, Qinghao Zhu, Ruowen Qiu, Zheng Ji Chen, Yinghao Yao, Qing Ren, Xiaoguang Yu, Jia Qu, Jianzhong Su, Jian Yuan","doi":"10.1136/jmg-2024-110467","DOIUrl":"10.1136/jmg-2024-110467","url":null,"abstract":"<p><strong>Background: </strong>High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. To understand the sex difference in the genetic architecture of HM, which may contribute to understanding HM aetiology and help further the realisation of precision medicine for HM.</p><p><strong>Methods: </strong>We performed sex-stratified exome-wide association studies (ExWAS) with n (males)=7492 and n (females)=8090, along with gene- and pathway-based tests and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to HM in a sex-specific manner.</p><p><strong>Results: </strong>In our ExWAS, we identified that a male-specific gene, <i>CHRNB1</i> (Z_females=1.382, P_females=0.083; Z_males=4.029, P_males=2.80×10^-05; P_difference=0.003), was associated with higher risk scores of HM in males than in females. Rare variant burden tests showed a significant excess of rare protein-truncating variants among HM males in <i>CHRNB1</i>-related pathways, including cell-cell signalling and muscle structure development. Sex-based differences in gene expression within <i>CHRNB1</i>-enriched ciliary body cells were observed; specifically, increased expression of mitochondrial metabolism-related genes in males and antioxidant genes in females. Functional differences in mitochondrial metabolism were confirmed in male-derived H1 and female-derived H9 human embryonic stem cell lines, with H1 cells specifically exhibiting significant dysregulation of mitochondrial organisation and mitochondrial respiratory chain complex assembly after <i>CHRNB1</i> knockdown.</p><p><strong>Conclusion: </strong>Together, our study provides insight into the sex differences in the genetic architecture of HM and highlights <i>CHRNB1</i>'s role in HM pathogenesis in males.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"358-368"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624999","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}