TY - JOUR
T1 - Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
AU - Groen, Karlijn
AU - van der Vis, Joanne J.
AU - van Batenburg, Aernoud A.
AU - Kazemier, Karin M.
AU - Grutters, Jan C.
AU - van Moorsel, Coline H.M.
N1 - Funding Information:
This study received funding from the St. Antonius Onderzoeksfonds. This study was also funded by ZonMW TopZorg St. Antonius Care (grant no. 842002001) and ZonMW Topspecialistische Zorg en Onderzoek (grant no. 10070012010004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - genetics
KW - idiopathic pulmonary fibrosis
KW - TDP1
KW - telomeres
KW - TOM1L2
UR - http://www.scopus.com/inward/record.url?scp=85147894809&partnerID=8YFLogxK
U2 - 10.3390/ijms24032790
DO - 10.3390/ijms24032790
M3 - Article
C2 - 36769106
AN - SCOPUS:85147894809
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 3
M1 - 2790
ER -