NACFC 2021 | S10: What Whole Genome Sequencing Teaches Us About Cystic Fibrosis

People with cystic fibrosis display variable disease severity across the CF affected organs and some of this variation can be explained by modifier genes, beyond the effect of their causal CFTR mutations.

Whole-genome sequencing (WGS) is revolutionizing our understanding of how genetic variation contributes to disease. The cost of WGS has now dropped sufficiently to enable short-read WGS to be implemented on large populations and provide the full 3 billion base pairs of the human genome on CF cohorts. Studying the whole genome, rather than genetic markers as was conventional in genome-wide association studies (GWAS), ensures the study of all types of variation -- such as copy number variation and rare variation -- can be investigated for their contribution to disease variation in CF.

However, not all regions of the genome can be sequenced using short-read WGS technology. Several that were identified through GWAS in CF localize to complex regions of the genome and the contributing genetic variation in the region remains unknown. Long- and linked-read genome sequencing technologies that sequence or link long molecules of DNA can span complex genomic regions. Although more costly, sequencing of cohorts using these WGS technologies enable de novo assembly and coverage of complex genomic regions to determine causal variation at these loci.

In this session, we hear from five speakers implementing whole-genome sequencing in CF to identify genetic contributors to CF disease.

Originally recorded November 3, 2021.