Journal of Medical Genetics最新文献

{"title":"Clinical and genetic characteristics of <i>PLA2G6</i>-related parkinsonism in Southwest China and a comprehensive literature review.","authors":"Yangfan Cheng, Yang Zhang, Yi Xiao, Shichan Wang, Sihui Chen, Xiaoting Zheng, Tianmi Yang, Qirui Jiang, Jingxuan Huang, Junyu Lin, Ruwei Ou, Chunyu Li, Qianqian Wei, Xueping Chen, Huifang Shang","doi":"10.1136/jmg-2024-110479","DOIUrl":"https://doi.org/10.1136/jmg-2024-110479","url":null,"abstract":"<p><strong>Background: </strong>Biallelic <i>PLA2G6</i> mutations are associated with early onset autosomal recessive parkinsonism, exhibiting a broad spectrum of clinical heterogeneity.</p><p><strong>Objective: </strong>To comprehensively characterise the clinical, imaging and genetic features of <i>PLA2G6</i>-related parkinsonism.</p><p><strong>Methods: </strong>We report 14 new cases of <i>PLA2G6</i>-related parkinsonism in Southwest China and conduct a systematic literature review.</p><p><strong>Results: </strong>Among the 14 patients in our cohort, 16 <i>PLA2G6</i> variants were identified, including seven novel and nine previously reported variants. The mean age at symptom onset was 26.50±6.57 years. The most common initial presentation was parkinsonism (9/14, 64.3%), followed by gait disturbance (6/14, 42.9%) and psychiatric symptoms (1/14, 7.1%). A literature review identified 118 patients with <i>PLA2G6</i>-related parkinsonism, with a mean age at onset of 24.53±8.84 years. The most common initial clinical features included parkinsonism (61/117, 52.1%), cerebellar signs (46/85, 54.1%), cognitive impairment (65/92, 70.7%) and psychiatric symptoms (80/93, 86.0%). Subgroup analysis showed that the mean age at symptom onset was older in Chinese patients (26.65±7.08 years) compared with those of European ancestry (20.83±9.79 years) (p=0.016). Additionally, patients of European ancestry showed delayed parkinsonism 5.35±8.14 years after onset. Iron deposition was reported more frequently in patients of European ancestry (10/16, 62.5%) than that in Chinese patients (6/37, 16.2%) (p=0.0002).</p><p><strong>Conclusion: </strong>Our study provides new insights on the diverse clinical spectrum of <i>PLA2G6</i>-related parkinsonism, encompassing parkinsonian features, psychiatric symptoms, cognitive impairment and early levodopa-induced motor complications.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975706","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":"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":"Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.","authors":"Victoria Lillback, Gaber Bergant, Maria Francesca Di Feo, Ivana Babić Bozović, Annalaura Torella, Mridul Johari, Aleš Maver, Katarina Pelin, Filippo M M Santorelli, Vincenzo Nigro, Peter Hackman, Borut Peterlin, Bjarne Udd, Marco Savarese","doi":"10.1136/jmg-2024-110212","DOIUrl":"10.1136/jmg-2024-110212","url":null,"abstract":"<p><strong>Background: </strong>Inherited rare skeletal muscle diseases cause muscle weakness and wasting of variable severity. Without a molecular diagnosis, patients often endure prolonged diagnostic journeys, leading to delays in appropriate management of the disease. This occurs in approximately 60% of patients with rare diseases.</p><p><strong>Methods: </strong>To facilitate reanalysis of 278 unsolved patients, we used a gene prioritisation tool Exomiser, which standardises analysis by ranking causative variants based on phenotype relevance and variant pathogenicity. Before analysis, we benchmarked Exomiser for variant prioritisation with solved cases and for novel disease gene discovery with mock cases with variants in candidate disease genes. Additionally, we studied the significance of the specificity of the phenotype descriptions.</p><p><strong>Results: </strong>In our study, Exomiser ranked genes in the top 10 correctly in 97.4% of controls with previously detected causative variants. Moreover, 57.1% of candidate genes in mock cases were similarly prioritised in the top 10. We also showed that three parental muscle disease human phenotype ontologies describing the patient phenotype performed as well as patient-specific ones, with a p value of 0.68 for difference in performance. The provided automation and standardisation of variant interpretation resulted in two novel diagnoses and in findings, either in known muscle disease genes or in novel candidate genes, which need further investigation.</p><p><strong>Conclusions: </strong>Exomiser is recommended for initial and periodic reanalyses of exomes in unsolved patients with myopathy, as it benefits from literature updates and minimises effort. This approach could also extend to whole genome sequencing data, aiding the interpretation of variants beyond coding regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"350-357"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566586","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":"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}