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

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 impac...

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Autores principales: Lazareva, Tatyana E., Barbitoff, Yury A., Nasykhova, Yulia A., Pavlova, Nadezhda S., Bogaychuk, Polina M., Glotov, Andrey S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671084/
https://www.ncbi.nlm.nih.gov/pubmed/38003043
http://dx.doi.org/10.3390/genes14112100
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author Lazareva, Tatyana E.
Barbitoff, Yury A.
Nasykhova, Yulia A.
Pavlova, Nadezhda S.
Bogaychuk, Polina M.
Glotov, Andrey S.
author_facet Lazareva, Tatyana E.
Barbitoff, Yury A.
Nasykhova, Yulia A.
Pavlova, Nadezhda S.
Bogaychuk, Polina M.
Glotov, Andrey S.
author_sort Lazareva, Tatyana E.
collection PubMed
description 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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spelling pubmed-106710842023-11-18 Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases Lazareva, Tatyana E. Barbitoff, Yury A. Nasykhova, Yulia A. Pavlova, Nadezhda S. Bogaychuk, Polina M. Glotov, Andrey S. Genes (Basel) Article 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. MDPI 2023-11-18 /pmc/articles/PMC10671084/ /pubmed/38003043 http://dx.doi.org/10.3390/genes14112100 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lazareva, Tatyana E.
Barbitoff, Yury A.
Nasykhova, Yulia A.
Pavlova, Nadezhda S.
Bogaychuk, Polina M.
Glotov, Andrey S.
Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title_full Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title_fullStr Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title_full_unstemmed Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title_short Statistical Dissection of the Genetic Determinants of Phenotypic Heterogeneity in Genes with Multiple Associated Rare Diseases
title_sort statistical dissection of the genetic determinants of phenotypic heterogeneity in genes with multiple associated rare diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671084/
https://www.ncbi.nlm.nih.gov/pubmed/38003043
http://dx.doi.org/10.3390/genes14112100
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