Journal of Medical Genetics最新文献

{"title":"Is renal cell carcinoma associated with <i>MITF</i> c.952G>A (p.E318K)?","authors":"Philip Harraka, Fiona Bruinsma, Tu Nguyen-Dumont, Susan Jordan, Graham G Giles, Ingrid M Winship, Kathy Tucker, Melissa C Southey","doi":"10.1136/jmg-2024-109984","DOIUrl":"10.1136/jmg-2024-109984","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"937-938"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875105","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":"Genotype-phenotype correlation of <i>SQSTM1</i> variants in patients with amyotrophic lateral sclerosis.","authors":"Shichan Wang, Qirui Jiang, Xiaoting Zheng, Qianqian Wei, Junyu Lin, Tianmi Yang, Yi Xiao, Chunyu Li, Huifang Shang","doi":"10.1136/jmg-2023-109569","DOIUrl":"10.1136/jmg-2023-109569","url":null,"abstract":"<p><strong>Background: </strong>Several variants of sequestosome 1 (<i>SQSTM1</i>) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear.</p><p><strong>Methods: </strong>We screened variants of <i>SQSTM1</i> gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of <i>SQSTM1</i> gene in patients with ALS from our cohort and published studies.</p><p><strong>Results: </strong>In our cohort, we identified 32 patients with 25 different <i>SQSTM1</i> variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with <i>SQSTM1</i> variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of <i>SQSTM1</i> variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in <i>SQSTM1</i>. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD.</p><p><strong>Conclusion: </strong>Our study established the largest cohort of patients with ALS with <i>SQSTM1</i> variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of <i>SQSTM1</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"966-972"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912979","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 sequencing identifies an SVA_D retrotransposon insertion deep within the intron of <i>ATP7A</i> as a novel cause of occipital horn syndrome.","authors":"Naoko Yano, Pin Fee Chong, Kenji K Kojima, Tomoichiro Miyoshi, Ahmad Luqman-Fatah, Yu Kimura, Kengo Kora, Taisei Kayaki, Kanako Maizuru, Takahiro Hayashi, Atsushi Yokoyama, Masahiko Ajiro, Masatoshi Hagiwara, Teruyuki Kondo, Ryutaro Kira, Junko Takita, Takeshi Yoshida","doi":"10.1136/jmg-2024-110056","DOIUrl":"10.1136/jmg-2024-110056","url":null,"abstract":"<p><strong>Background: </strong>SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A.</p><p><strong>Methods: </strong>We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses.</p><p><strong>Results: </strong>A 2.8 kb insertion was detected deep within the intron of the patient's <i>ATP7A</i> gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago.</p><p><strong>Conclusion: </strong>This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"950-958"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498188","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":"Development and internal validation of a clinical risk score to predict incident renal and pulmonary tumours in people with tuberous sclerosis complex.","authors":"Frédéric Loubert, Andrew A House, Catherine Larochelle, Philippe Major, Mark R Keezer","doi":"10.1136/jmg-2023-109717","DOIUrl":"10.1136/jmg-2023-109717","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to develop and internally validate a clinical risk score to predict incident renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) in people with tuberous sclerosis complex (TSC).</p><p><strong>Study design: </strong>Data from 2420 participants in the TSC Alliance Natural History Database were leveraged for these analyses. Logistic regression was used to predict AML and LAM development using 10 early-onset clinical manifestations of TSC as potential predictors, in addition to sex and genetic mutation. For our models, we divided AML into three separate outcomes: presence or absence of AML, unilateral or bilateral and whether any are ≥3 cm in diameter. The resulting regression models were turned into clinical risk scores which were then internally validated using bootstrap resampling, measuring discrimination and calibration.</p><p><strong>Results: </strong>The lowest clinical risk scores predicted a risk of AML and LAM of 1% and 0%, while the highest scores predicted a risk of 99% and 73%, respectively. Calibration was excellent for all three AML outcomes and good for LAM. Discrimination ranged from good to strong. C-statistics of 0.84, 0.83, 0.83 and 0.92 were seen for AML, bilateral AML, AML with a lesion≥3 cm and LAM, respectively.</p><p><strong>Conclusion: </strong>Our work is an important step towards identifying individuals who could benefit from preventative strategies as well as more versus less frequent screening imaging. We expect that our work will allow for more personalised medicine in people with TSC. External validation of the risk scores will be important to confirm the robustness of our findings.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"943-949"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558892","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":"Double gonosomal mosaicism as an unusual hereditary mechanism in familial <i>GRIN2A</i>-related disorder.","authors":"Valentina Cetica, Mara Cavallin, Maria Luisa Ricci, Claudia Mandorlini, Emanuele Bartolini, Elena Parrini, Renzo Guerrini","doi":"10.1136/jmg-2024-110101","DOIUrl":"10.1136/jmg-2024-110101","url":null,"abstract":"<p><p>We aim to describe double gonosomal mosaicism in the <i>GRIN2A</i> gene in a mother who passed on two different pathogenic variants at the same nucleotide to her two affected children. We studied a boy with epilepsy and intellectual disability, along with his sister and mother who exhibited language impairment and learning difficulties without epilepsy. We identified in the proband a splice-site variant in <i>GRIN2A</i> (c.1008-1G>A) inherited from his mother. Subsequent testing of his sister revealed a different change at the same nucleotide c.1008-1G>T, which was also present in the mother's DNA at 3.9% allele frequency. The co-occurrence of two mutational events at the same nucleotide is extremely rare. Since a chance occurrence is unlikely, we hypothesise that a base mismatch may introduce instability triggering a second event. In this family, the mother carries three alleles, of which one is at very low frequency. This complex genetic landscape poses diagnostic challenges since low-level mosaicism may escape detection via conventional methods. Applying specific technology becomes crucial, as double mosaicism might prove to be more prevalent than anticipated severely impacting diagnostic accuracy and genetic counselling.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"999-1002"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859963","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":"Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).","authors":"David S Moura, Daniel López López, Davide di Lernia, Marta Martin-Ruiz, Maria Lopez-Alvarez, Rafael Ramos, Jose Merino, Joaquin Dopazo, Jose Lopez-Guerrero, Jose L Mondaza-Hernandez, Pablo Romero, Nadia Hindi, Jesus Garcia-Foncillas, Javier Martin-Broto","doi":"10.1136/jmg-2024-110109","DOIUrl":"10.1136/jmg-2024-110109","url":null,"abstract":"<p><strong>Background: </strong>Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in <i>KIT</i> and <i>PDGFRA</i> genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.</p><p><strong>Methods: </strong>Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.</p><p><strong>Results: </strong>Both patients harbouring low-risk GISTs with different mutations (<i>PDGFRA</i> and <i>KIT</i>) shared homozygous germline pathogenic deletions in both <i>CFHR1</i> and <i>CFHR3</i> genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as <i>SLC25A24</i>. No particular pathogenic SNV shared by both patients was detected.</p><p><strong>Conclusion: </strong>Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, <i>CFHR1</i> and <i>CFHR3</i> deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"927-934"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995906","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":"Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients.","authors":"Hortense Thomas, Tom Alix, Émeline Renard, Mathilde Renaud, Justine Wourms, Stéphane Zuily, Bruno Leheup, David Geneviève, Natacha Dreumont, Emmanuelle Schmitt, Myriam Bronner, Marc Muller, Marion Divoux, Marion Wandzel, Jean-Marie Ravel, Mylène Dexheimer, Aurélie Becker, Virginie Roth, Marjolaine Willems, Christine Coubes, Gaëlle Vieville, Françoise Devillard, Élise Schaefer, Sarah Baer, Amélie Piton, Bénédicte Gérard, Marie Vincent, Mathilde Nizon, Benjamin Cogné, Lyse Ruaud, Nathalie Couque, Audrey Putoux, Patrick Edery, Gaëtan Lesca, Nicolas Chatron, Marianne Till, Laurence Faivre, Frédéric Tran-Mau-Them, Jean-Luc Alessandri, Marine Lebrun, Chloé Quélin, Sylvie Odent, Christèle Dubourg, Véronique David, Marie Faoucher, Cyril Mignot, Boris Keren, Élise Pisan, Alexandra Afenjar, Sophie Julia, Éric Bieth, Guillaume Banneau, Alice Goldenberg, Thomas Husson, Dominique Campion, François Lecoquierre, Gaël Nicolas, Camille Charbonnier, Anne De Saint Martin, Sophie Naudion, Manon Degoutin, Sophie Rondeau, Caroline Michot, Valérie Cormier-Daire, Abderrahim Oussalah, Carine Pourié, Laëtitia Lambert, Céline Bonnet","doi":"10.1136/jmg-2024-110031","DOIUrl":"10.1136/jmg-2024-110031","url":null,"abstract":"<p><strong>Background: </strong>Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (<i>DNMT3A</i>)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in <i>DNMT3A</i>, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of <i>DNMT3A</i> are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.</p><p><strong>Methods: </strong>We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.</p><p><strong>Results: </strong>Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in <i>DNMT3A</i>, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.</p><p><strong>Conclusion: </strong>This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"878-885"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468659","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":"Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome.","authors":"Vicken Totten, Gisela Teixido-Tura, Fermina Lopez-Grondona, Paula Fernandez-Alvarez, Amaia Lasa-Aranzasti, Patricia Muñoz-Cabello, Rika Kosaki, Eduardo F Tizzano, Wendy Dewals, Emma Borràs, Elena Gonzalez Cañas, Berta Almoguera, Bart Loeys, Irene Valenzuena","doi":"10.1136/jmg-2024-109861","DOIUrl":"10.1136/jmg-2024-109861","url":null,"abstract":"<p><strong>Background: </strong>Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by <i>DNMT3A</i> heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described.</p><p><strong>Methods: </strong>Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition.</p><p><strong>Results: </strong>We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery.</p><p><strong>Conclusions: </strong>Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"870-877"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498187","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":"Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation.","authors":"Alessandro Geroldi, Alessia Mammi, Andrea Gaudio, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Sara Massucco, Lucio Marinelli, Marina Grandis, Angelo Schenone, Paola Mandich, Emilia Bellone, Fabio Gotta","doi":"10.1136/jmg-2024-110019","DOIUrl":"10.1136/jmg-2024-110019","url":null,"abstract":"<p><strong>Background: </strong>The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.</p><p><strong>Methods: </strong>We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.</p><p><strong>Results: </strong>Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.</p><p><strong>Conclusions: </strong>The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"847-852"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317551","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":"Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.","authors":"Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang","doi":"10.1136/jmg-2024-109909","DOIUrl":"10.1136/jmg-2024-109909","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS.</p><p><strong>Methods: </strong>Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.</p><p><strong>Results: </strong>A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).</p><p><strong>Conclusion: </strong>Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"839-846"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419441","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}