Abstract
Cystic fibrosis (CF) is a monogenic disease characterized by a high variability of disease severity and outcome that points to the role of environmental factors and modulating genes that shape the course of this multiorgan disease. We genotyped families of cystic fibrosis sib pairs homozygous for F508del-CFTR who represent extreme clinical phenotypes at informative microsatellite markers spanning a 38 Mb region between CFTR and 7qtel. Recombination events on both parental chromosomes were compared between siblings with concordant clinical phenotypes and siblings with discordant clinical phenotypes. Monitoring parent-of-origin-specific decay of genomic sharing delineated a 2.9-Mb segment on 7q34 in which excess of recombination on paternal chromosomes in discordant pairs was observed compared with phenotypically concordant sibs. This 2.9-Mb core candidate region was enriched in imprinting-related elements such as predicted CCCTC-binding factor consensus sites and CpG islands dense in repetitive elements. Moreover, allele frequencies at a microsatellite marker within the core candidate region differed significantly comparing mildly and severely affected cystic fibrosis sib pairs. The identification of this paternally imprinted locus on 7q34 as a modulator of cystic fibrosis disease severity shows that imprinted elements can be identified by straightforward fine mapping of break points in sib pairs with informative contrasting phenotypes.