Journal of Medical Genetics最新文献

{"title":"Clinicogenetic characterisation of SLC29A3-related syndromes: a case series, tracing ancestral variants and molecular dynamics simulation.","authors":"Sajjad Biglari, Mohammad Shahrooei, Fatemeh Vahidnezhad, Leila Youssefian, Vahid Ziaee, Nima Rezaei, Atefeh Sohanforooshan Moghaddam, Sahar Sedighzadeh, Hossein Moravej, Parisa Safari Foroushani, Majid Keivanfar, Homa Ilkhanipoor, Amir Hozhabrpour, Hooria Seyedhosseini-Ghaheh, Iraj Mohammadzadeh, Majid Naderi, Elham Sheikhi Ghayur, Nader Mansour Samaei, Saeed Dorgaleleh, Emran Esmaeilzadeh, Roya Sherkat, Hamid Reza Khorram Khorshid, Mohammad Amin Tabatabaiefar, Hakon Hakonarson, Hassan Vahidnezhad","doi":"10.1136/jmg-2024-110606","DOIUrl":"10.1136/jmg-2024-110606","url":null,"abstract":"<p><strong>Background: </strong>SLC29A3-related syndromes (SLC29A3-RS) are characterised by severe and multiorgan involvement that has a severe impact on the quality of life of the affected persons and therefore merit further genetic and clinical research. We investigated the clinical and genetic aspects of patients with SLC29A3-RS.</p><p><strong>Methods: </strong>Six pathogenic variants of the <i>SLC29A3</i> gene were identified in eight families in the current study. RNA sequencing was used for evaluating <i>SLC29A3</i> variant gene expression and protein stability by molecular dynamics (MD) simulations. This study conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of cases across five electronic databases.</p><p><strong>Results: </strong>Genetic analysis revealed six pathogenic variants of the <i>SLC29A3</i> gene in eight families; one variant was shared among three families, indicating a possible founder effect. The estimated most recent common ancestor for these patients lived approximately 8.5 generations ago. MD studies revealed structural instability in mutant proteins. RNA sequencing also demonstrated that the expression of SLC29A3 was downregulated while the expression of the immune markers CD68 and LYZ was upregulated. A systematic search of 197 patients of different ethnic backgrounds revealed that the following symptoms were frequent findings: hyperpigmentation, hypertrichosis, hearing loss, short stature and hepatomegaly. The age of onset of SLC29A3-RS was 5.53±5.24 years with an IQR of 1.4-8.25 years.</p><p><strong>Conclusions: </strong>The characterisation of the founder variants and the genotype-phenotype correlations helps delineate the phenotype spectrum of SLC29A3-RS, which will facilitate the genetic counselling and screening of the high-risk population. Findings on <i>SLC29A3</i> variants show the way to proceed in the process of developing the diagnostic and therapeutic methods in the management of SLC29A3-RS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"369-380"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657470","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":"De novo heterozygous missense variants in <i>ATP11A</i> are associated with refractory focal epilepsy.","authors":"Zi-Long Ye, Nan-Xiang Shen, Xiang-Yun Luo, Hai-Sheng Lin, Yu-Tao Guo, Dong-Jie Qiu, Shi-Zhan Yuan, Ming-Feng He, Cui-Xia Fan, Wen-Bin Li, Yi-Wu Shi, Li-Bin Zhang","doi":"10.1136/jmg-2024-110540","DOIUrl":"10.1136/jmg-2024-110540","url":null,"abstract":"<p><strong>Background: </strong><i>ATP11A</i> encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays an important role in neural development by maintaining membrane lipid asymmetry. <i>ATP11A</i> de novo heterozygous missense variants have been reported to be associated with hypomyelinating leukodystrophy; however, the neurological symptoms of patients are often varying. In this study, we aimed to explore the relationship between <i>ATP11A</i> variants and epilepsy.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed on patients with focal epilepsy. Multiple bioinformatics analyses were used to predict the pathogenicity of the variants. Previously reported literature was collected to analyse the relation between variants and phenotypes.</p><p><strong>Results: </strong>Two de novo heterozygous missense variants of <i>ATP11A</i> were identified in two unrelated patients with refractory focal epilepsy and were predicted to be pathogenic using multiple bioinformatics analyses. Then, six patients associated with missense variants were collected. Half of the patients (3/6) with variants located on/near the transmembrane regions (TMs) had more severe and multiple neurological symptoms, while the other half with non-TM variants had mild and single symptoms, indicating a correlation between variant location and phenotype. All patients showed progressively worsening conditions, potentially due to a gradually increased expression of <i>ATP11A</i> in the human brain over time.</p><p><strong>Conclusion: </strong>This study suggested that de novo heterozygous missense variants of <i>ATP11A</i> are associated with refractory focal epilepsy. Missense variant-associated phenotypes range from epileptic seizures to severe neurological symptoms. It should be noted that patients with <i>ATP11A</i> variants have a gradually worsening potential.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"396-404"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788524","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":"Analysing tumours for genetic diagnosis in mosaic neurofibromatosis type 1.","authors":"Tabea Isabelle Hartung, Lan Kluwe, Said Chosro Farschtschi","doi":"10.1136/jmg-2024-110580","DOIUrl":"10.1136/jmg-2024-110580","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder caused by pathogenic variants in the <i>NF1</i> gene, resulting in diverse clinical manifestations, especially multiple cutaneous neurofibromas. In approximately 50% of cases, variants occur de novo, and a portion of these cases involves genetic mosaicism, where variants are present in a subset of cells of an individual. Mosaic NF1 often presents with a milder phenotype and reduced transmission risk, complicating clinical diagnosis and genetic consulting. Conventional blood-based genetic testing may fail to detect the pathogenic variants in mosaic cases, necessitating additional analysis using tumour-derived DNA. We present five such cases and suggest a comprehensive diagnostic workflow focusing on tumour-based analysis for mosaic cases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"405-408"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729946","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":"Six at Sixty. Commentary on osteogenesis imperfecta 1975-2025.","authors":"David Sillence","doi":"10.1136/jmg-2025-110807","DOIUrl":"10.1136/jmg-2025-110807","url":null,"abstract":"<p><p>Between 1975 and 1977, my collaborators and I conducted a whole-of-population study in Victoria, Australia, examining the various presentations and clinical manifestations of osteogenesis imperfecta (OI) and familial forms of bone fragility. In 1975, the prevailing view was that all presentations of OI reflected variable expression of pathogenic genomic variants at a single gene locus-possibly involving the recently identified protein, type I collagen. We concluded that OI was in fact genetically heterogeneous, setting the scene for future biochemical and genomic discoveries. Currently, OI is recognised to result from pathological variants in >20 genes, with variants in many further loci resulting in related forms of familial osteoporosis or special syndromes characterised by bone fragility. A dyadic nosology has been adopted to help clinicians, researchers and affected individuals in accessing OI diagnosis, treatment and research with a focus on precision medicine.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 6","pages":"422-426"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159486","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":"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}

{"title":"Impact of NICE Guideline NG241 'Ovarian Cancer: identifying and managing familial and genetic risk' on a regional NHS family history and clinical genetics service.","authors":"Alexander Roe, Andrea Forman, Fiona Lalloo, Terri P McVeigh, Helen Hanson, Katie Snape","doi":"10.1136/jmg-2024-110481","DOIUrl":"10.1136/jmg-2024-110481","url":null,"abstract":"<p><strong>Background: </strong>NICE Guideline NG241: identifying and managing familial and genetic risk of ovarian cancer (OC) was published by the National Institute for Health and Care Excellence (NICE) in March 2024. NG241 advises germline genetic testing of genes predisposing to OC in unaffected individuals with an OC family history at different mutation likelihood thresholds depending on age and sex, ranging from 2% to 10% likelihood of finding a germline pathogenic variant (GPV). Prior to implementation of NG241, updates to the NHS England National Genomic Test Directory would be required. Clinical genetics services have to consider equity of access to assessment and testing across all familial cancer types, best use of their limited resources and other factors such as complexity of delivery of clinical pathways.</p><p><strong>Methods: </strong>We analysed data from 8011 patients who provided digital family histories to the South West Thames Centre for Genomics between October 2019 and June 2024.</p><p><strong>Results: </strong>We estimate 527/782 (68%) females and 28/77 (36%) males would meet test criteria for NICE NG241. We estimate we would reject 2919/5485 (53%) females and 135/1208 (11%) males with the same likelihood of carrying a GPV, but with a breast cancer rather than OC family history. Testing the familial OC cohort at a universal 5% threshold in OC families would detect ~11 carriers for 229 tests compared with ~8 carriers for 278 tests following NG241 criteria.</p><p><strong>Conclusion: </strong>Our data highlight additional factors needing to be considered before the NICE Guideline NG241 can be implemented by regional genetics services.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"311-316"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458222","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":"Homozygous loss of function variant in <i>LMNB2</i> gene causes major brain malformation and perinatal death.","authors":"Camille Desgrouas, Igor Deryabin, Clémence Duvillier, Diane Frankel, Elise Kaspi, Thibaud Quibel, Gabriel Le Goff, Mathieu Cerino, Jérémie Mortreux, Bénédicte Gérard, Rodolphe Dard, Catherine Badens","doi":"10.1136/jmg-2024-110549","DOIUrl":"10.1136/jmg-2024-110549","url":null,"abstract":"<p><p>Lamins play a major role in the mechanical stability of cell nuclei, the organisation of chromatin and the DNA replication, transcription and repair. The expression profiles of A-type and B-type lamins vary depending on developmental stages, cell types and tissues. Lamin B2 is expressed very early in embryogenesis, especially in the central nervous system, where it is essential for neuronal migration and brain development. Pathogenic missense variants in lamin B2 have been linked to conditions such as lipodystrophy, progressive myoclonic epilepsy and primary microcephaly. Here, we report clinical data and molecular findings for two related newborns carrying a homozygous loss-of-function variant in the <i>LMNB2</i> gene. Both newborns died in the perinatal period and exhibited a similar phenotype at birth, including severe brain development abnormalities, which closely mirror findings observed in several <i>Lmnb2</i>-deficient mouse models. Western blot and immunofluorescence cell labelling performed on the patient's fibroblasts obtained at birth confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. This novel clinical form of laminopathy associated with lamin B2 deficiency expands the molecular causes of brain development abnormalities to <i>LMNB2</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"345-349"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515904","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}