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Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis

In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF pati...

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Autores principales: Groen, Karlijn, van der Vis, Joanne J., van Batenburg, Aernoud A., Kazemier, Karin M., Grutters, Jan C., van Moorsel, Coline H. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917193/
https://www.ncbi.nlm.nih.gov/pubmed/36769106
http://dx.doi.org/10.3390/ijms24032790
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author Groen, Karlijn
van der Vis, Joanne J.
van Batenburg, Aernoud A.
Kazemier, Karin M.
Grutters, Jan C.
van Moorsel, Coline H. M.
author_facet Groen, Karlijn
van der Vis, Joanne J.
van Batenburg, Aernoud A.
Kazemier, Karin M.
Grutters, Jan C.
van Moorsel, Coline H. M.
author_sort Groen, Karlijn
collection PubMed
description In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: TOM1L2 c.421T > C p.(Y141H) and TDP1c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality.
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spelling pubmed-99171932023-02-11 Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis Groen, Karlijn van der Vis, Joanne J. van Batenburg, Aernoud A. Kazemier, Karin M. Grutters, Jan C. van Moorsel, Coline H. M. Int J Mol Sci Article In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: TOM1L2 c.421T > C p.(Y141H) and TDP1c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality. MDPI 2023-02-01 /pmc/articles/PMC9917193/ /pubmed/36769106 http://dx.doi.org/10.3390/ijms24032790 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
Groen, Karlijn
van der Vis, Joanne J.
van Batenburg, Aernoud A.
Kazemier, Karin M.
Grutters, Jan C.
van Moorsel, Coline H. M.
Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title_full Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title_fullStr Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title_full_unstemmed Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title_short Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
title_sort genetic variant overlap analysis identifies established and putative genes involved in pulmonary fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917193/
https://www.ncbi.nlm.nih.gov/pubmed/36769106
http://dx.doi.org/10.3390/ijms24032790
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