The genetics and genomics of cystic fibrosis

Abstract

Genetics is the branch of biology concerned with study of individual genes and how they work whereas genomics is involved with the analysis of all genes and their interactions. Both of these approaches have been applied extensively to CF. Identification of the CFTR gene initiated the dissection of CF genetics at the molecular level. Subsequently, thousands of variants were found in the gene and the functional consequences of a subset have been studied in detail. The completion of the human genome ushered in a new phase of study where the role of genes beyond CFTR could be evaluated for their contribution to the severity of CF. This will be a brief overview of the contribution of these complementary methods to our understanding of CF pathogenesis.

Keywords: Association; CFTR; Cystic fibrosis; Genetic modifiers; Linkage.

Fig. 1.

Genetic variants in CFTR and their impact on RNA and protein production. Only a portion of CFTR gene is shown. Rectangular boxes are exons, dashed lines are either introns, 5′UTR or 3′UTR, and dashed hashes are multiple exon-introns within CFTR gene. Please note, only few nucleotides within each exon are shown. Dinucleotides, gt and ag, in black letters represent consensus splice site signals. Alphabets in red beneath each exon or intron represent nucleotide changes. Variant names are written beneath each nucleotide change. Nonsense and frameshift variants can have heterogeneous effects on mRNA stability depending upon their location [13]. Misfolded CFTR protein undergoes ER-associated degradation via the ubiquitin–proteasome system. Fully glycosylated mature protein can be dysfunctional due to impaired gating, conductance or reduced residence time at the cell surface [4]. Missense variants predicted to make mature protein can undergo mis-splicing resulting in no protein or immature dysfunctional CFTR protein [–11]. *indicates in-frame mis-spliced mRNA may also generate mature but dysfunctional CFTR protein.

Fig. 2.

Relative contribution of genetic and non-genetic factors by organ system to variation in cystic fibrosis traits (adapted from Reference [33]). The magnitude of effect of CFTR, modifier genes and environment to variation in each trait were derived from CF twin and sibling analysis. Select modifier genes and loci implicated by candidate, linkage, association or exome sequencing methods are shown.