دورية أكاديمية
أعرض في EDS

Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases.

التفاصيل البيبلوغرافية
العنوان: Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases.
المؤلفون: Lazareva TE; Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynaecology, and Reproductology, 199034 St. Petersburg, Russia., Barbitoff YA; Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynaecology, and Reproductology, 199034 St. Petersburg, Russia.; Bioinformatics Institute, Kantemirovskaya St. 2A, 197342 St. Petersburg, Russia., Nasykhova YA; Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynaecology, and Reproductology, 199034 St. Petersburg, Russia., Pavlova NS; Bioinformatics Institute, Kantemirovskaya St. 2A, 197342 St. Petersburg, Russia., Bogaychuk PM; Bioinformatics Institute, Kantemirovskaya St. 2A, 197342 St. Petersburg, Russia., Glotov AS; Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynaecology, and Reproductology, 199034 St. Petersburg, Russia.
المصدر: Genes [Genes (Basel)] 2023 Nov 18; Vol. 14 (11). Date of Electronic Publication: 2023 Nov 18.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel : MDPI
مواضيع طبية MeSH: Rare Diseases*/genetics, Humans ; Phenotype ; Prognosis
مستخلص: Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene-disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene-disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity.
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معلومات مُعتمدة: contract No. 075-15-2021-1058 Ministry of Science and Higher Education of the Russian Federation
فهرسة مساهمة: Keywords: genetic variants; phenotypic heterogeneity; rare disease; variant interpretation; variant localization
تواريخ الأحداث: Date Created: 20231125 Date Completed: 20231127 Latest Revision: 20240620
رمز التحديث: 20240620
مُعرف محوري في PubMed: PMC10671084
DOI: 10.3390/genes14112100
PMID: 38003043
قاعدة البيانات: MEDLINE
الوصف
تدمد:2073-4425
DOI:10.3390/genes14112100