Cystic Fibrosis Carrier Testing in an Ethnically Diverse US Population

Abstract

BACKGROUND:The incidence of cystic fibrosis (CF) and the frequency of specific disease-causing mutations vary among populations. Affected individuals experience a range of serious clinical consequences, notably lung and pancreatic disease, which are only partially dependent on genotype.

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

“…[8][9][10] The carrier frequency of the most frequent AJ mutation, c.3846G>A (p.W1282X) in ExAC was 1/1312, which is lower than the reported carrier frequency of 1/863 for this CFTR variant in an ethnically diverse US population (P < 0.05). 11 This indicates that the AJ ethnicity is not overrepresented in the ExAC data set. Likewise, the three most frequent pathogenic CFTR variants observed in ExAC were c.1521_1523delCTT (p.F508del), c.350G>A (p.R117H), and c.3209G>A (p.R1070Q), each with a carrier frequency of 1/74, 1/325, and 1/619, respectively.…”

“…Of these, the carrier frequency of p.F508del and p.R117H in ExAC were in range of the reported frequency for p.F508del (1/65) and p.R117H (1/422) in an ethnically diverse US population. 11 Within the subpopulations represented in ExAC, the carrier frequencies of these three most frequent pathogenic CFTR variants are highest in non-Finnish Europeans (1/47) for p.F508del, in non-Finnish Europeans (1/195) for p.R117H, and in South Asians (1/95) for p.R1070Q. The overall distribution pattern of these variants within different ethnicities is consistent with published data among African, Asian, Caucasian, Latino, and other populations.…”

“…The overall distribution pattern of these variants within different ethnicities is consistent with published data among African, Asian, Caucasian, Latino, and other populations. 11,12 Furthermore, the distribution of pathogenic variants with homozygous occurrences in GJB2 (p.V37I and c.35delG in East Asians and Europeans, respectively), HBB (p.E7K and p.E7V in Africans), and MEFV (p.V726A in Europeans) followed the expected distribution based upon the reported prevalence of autosomal recessive deafness (GJB2, OMIM 220290), hemoglobinopathies (HBB, OMIM 141900), and Familial Mediterranean Fever (MEFV, OMIM 249100) in these subpopulations. [13][14][15] These observations demonstrate that ExAC is not overenriched for pathogenic variants in the specific disorders tested, thereby supporting its utility as a control cohort in genetic analysis.…”

Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk

“…Carrier screening was performed with four targeted mutation panels: the ACMG-recommended core panel with 23 mutations, 7 the Integrated Genetics CFplus panel with 92 CFTR mutations, 9 the Counsyl Family Prep Screen 1.0 panel with 103 CFTR mutations, 8 and the Recombine CarrierMap panel with 108 CFTR mutations (http://www.recombine.com, accessed on 20 January 2015). In addition, mock screening was performed with the hypothetical targeted mutation panel representing the 159 variants characterized by Sosnay et al 11 in genomes from the CFTR2 patient cohort.…”

“…7 Since the establishment of the core ACMG panel, numerous commercial laboratories have produced expanded genetic panels of 90 or more CFTR variants, including those designed by the genetic testing companies Integrated Genetics, Counsyl, and Recombine. 8,9 Original research article Although DNA genotyping can be extraordinarily accurate from an analytical perspective, it is not sufficient by itself for determination of downstream effects of gene function and prediction of phenotypes in hypothesized homozygous or compound heterozygous individuals (see Cooper et al for a review 10 ). This is especially true for diseases with continuous phenotypes, like CF.…”