Mutation Distribution in Expanded Screening for Cystic Fibrosis: Making Up the Balance in a Context of Ethnic Diversity

Abstract

Cystic fibrosis (CF)2 (OMIM 219700) is a serious autosomal recessive condition that primarily affects the respiratory, gastrointestinal, and reproductive organ systems. Its pathophysiology is due to dysfunctional regulation of chloride ion channels precipitated by mutations in the CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] gene (OMIM *602421). CF is typically associated with considerable morbidity and a reduced life expectancy, although phenotypic variability is the norm. This variation is largely due to differences in the combination of underlying molecular defects, but it also stems from the effects of modifying genes, the environment, and complications (1). At one end of the phenotypic spectrum, affected individuals may have very mild manifestations that are isolated to single organ systems, whereas the disease at the other end involves an early demise (2). CF affects populations across the globe but is most common in northern European whites (approximately 1 in 2500 individuals) and in Ashkenazi Jews (approximately 1 in 2270) (3–5). In the ethnically diverse population of the US, CF is diagnosed in approximately 1 in 3900 individuals (6). The Cystic Fibrosis Genetic Analysis Consortium database includes 1865 CFTR sequence variants (7). Of these variants, p.F508del is the most common mutation; it accounts for nearly two-thirds of the mutations overall. The remaining alleles, many of which are rare, are widely distributed, predominantly in the coding sequence, and demonstrate striking heterogeneity. Both the spectrum and the frequency of individual CFTR sequence changes vary considerably among different ethnic/geographic populations, although much remains to be learned about CFTR mutations in US minorities (8, 9). This situation primarily reflects the fact that these populations have not yet been studied as thoroughly as whites; however, it may also be due in part to the possibility that mutations not typically identified by …