Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis.

Autor:	Wilk MA; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA., Braun AT; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA., Farrell PM; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA., Laxova A; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA., Brown DM; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA., Holt JM; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA., Birch CL; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA., Sosonkina N; Department of Genetics, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA., Wilk BM; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA., Worthey EA; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.; Department of Genetics, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA.
Jazyk:	angličtina
Zdroj:	Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2020 Feb 03; Vol. 6 (1). Date of Electronic Publication: 2020 Feb 03 (Print Publication: 2020).
DOI:	10.1101/mcs.a004531
Abstrakt:	Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis. (© 2020 Wilk et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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