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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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2790 |
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| author | Karlijn Groen Joanne J. van der Vis Aernoud A. van Batenburg Karin M. Kazemier Jan C. Grutters Coline H. M. van Moorsel |
| author_facet | Karlijn Groen Joanne J. van der Vis Aernoud A. van Batenburg Karin M. Kazemier Jan C. Grutters Coline H. M. van Moorsel |
| author_sort | Karlijn Groen |
| collection | DOAJ |
| 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: <i>TOM1L2</i> c.421T > C p.(Y141H) and <i>TDP1</i>c.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. |
| first_indexed | 2024-03-11T09:39:48Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:39:48Z |
| publishDate | 2023-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5204ff50724543c78727e101082c92db2023-11-16T17:02:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01243279010.3390/ijms24032790Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary FibrosisKarlijn Groen0Joanne J. van der Vis1Aernoud A. van Batenburg2Karin M. Kazemier3Jan C. Grutters4Coline H. M. van Moorsel5Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The NetherlandsDepartment of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The NetherlandsDepartment of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The NetherlandsCenter of Translational Immunology, University Medical Center Utrecht, 3508 GA Utrecht, The NetherlandsDepartment of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The NetherlandsDepartment of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The NetherlandsIn 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: <i>TOM1L2</i> c.421T > C p.(Y141H) and <i>TDP1</i>c.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.https://www.mdpi.com/1422-0067/24/3/2790idiopathic pulmonary fibrosisgeneticstelomeres<i>TDP1</i><i>TOM1L2</i> |
| spellingShingle | Karlijn Groen Joanne J. van der Vis Aernoud A. van Batenburg Karin M. Kazemier Jan C. Grutters Coline H. M. van Moorsel Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis International Journal of Molecular Sciences idiopathic pulmonary fibrosis genetics telomeres <i>TDP1</i> <i>TOM1L2</i> |
| 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 | idiopathic pulmonary fibrosis genetics telomeres <i>TDP1</i> <i>TOM1L2</i> |
| url | https://www.mdpi.com/1422-0067/24/3/2790 |
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