Carrier frequency of CFTR variants in the non‐Caucasian populations by genome aggregation database (gnomAD)‐based analysis

Abstract

The complexity in the molecular diagnosis of Cystic Fibrosis (CF) also depends on the variable prevalence/incidence of the disease associated with the wide CFTR allelic heterogeneity among different populations. In fact, CF incidence in Asian and African countries is underestimated and the few patients reported so far have rare or unique CFTR pathogenic variants. To obtain insights into CF variants profile and frequency, we used the large population sequencing data in the Genome Aggregation Database (gnomAD). We selected 207 CF-causing/varying clinical consequence variants from CFTR2 database and additional 15 variants submitted to the ClinVar database. Only 14 of these variants were found in the East-Asian population, while for South-Asian and African populations we identified 43 and 52 variants, respectively, confirming the peculiarity of the CFTR allelic spectrum with only few population-specific variants. These data could be used to optimize CFTR carrier screening in non-Caucasian subjects, choosing between the full gene sequencing and cost and time-effective targeted panels.

Summix: A method for detecting and adjusting for population structure in genetic summary data

“…While many of these studies are in European [39][40][41] or East Asian 42,43 ancestral groups, which we find to contain little to no other continental reference ancestry, some studies use gnomAD groups that contain admixture (e.g., African/African American, American/Latinx, and South Asian) for comparison without adjusting population structure. 6,16,44 We evaluate the potential utility of Summix's ancestryadjusted AF by producing ancestry-adjusted AFs for Clin-Var variants, for the CF variant p.Phe508del in CFTR, and for a case-control analysis of PADI3, a gene where gno-mAD was used as an external control sample to identify as-sociation with central centrifugal cicatricial alopecia in women with African ancestry. Although we find mostly minor discrepancies in the unadjusted and ancestryadjusted AFs, we note that these differences can affect evidence of association for case-control analysis, as we demonstrate in PADI3, and prioritization of putative causal variants for follow up.…”

“…Nappo et al use gnomAD v.2.1 to estimate the prevalence of CFTR (MIM: 602421) variants defined as cystic fibrosis (CF [MIM: 219700])-causing or varying clinical consequence in non-European populations, including South Asian and African/African American. 16 To highlight Summix's utility in providing more precise AF adjusting for ancestry, we provide ancestry-adjusted AF for a 100% African target sample for p.Phe508del (c.1521_1523delCTT), the most common CF variant.…”

“…To evaluate the prevalence of CF variants in non-European ancestral populations, Nappo et al report the AF for CFTR variants with causal or varying clinical consequence in non-European ancestral groups from gnomAD v.2.1, such as African/African American and South Asian. 16 As another exemplar of the utility for ancestry-adjusted AF, we estimated the adjusted AF for the most common CF variant, p.Phe508del, for the African/African American group assuming 100% African ancestry. As expected, given the higher AF in the non-Finnish European ancestry, the ancestry-adjusted AF is smaller than the unadjusted AF for both exome and genome African/African American groups (Table S16).…”

“…As a result, researchers and clinicians working with these populations are often left with a suboptimal choice: use the closest but still poorly matched ancestral group or do not use the publicly available and highly useful resource. 6,16 The former has the potential to produce biased results in the very populations where additional high-quality research is needed, while the latter is likely to suffer from smaller sample sizes and thus a loss of statistical power. This choice exacerbates inequities in research in understudied and admixed populations.…”

Prenatal Ultrasound Suspicion of Cystic Fibrosis in a Multiethnic Population: Is Extensive CFTR Genotyping Needed?

“…The mutation remained unknown in 56.5% [ 38 ]. While the disparity in identified mutations in non-Caucasian populations versus Caucasian populations has been known for a long time, Nappo et al recently objectified it thanks to the numerous information of the Genome Aggregation Database (gnomAD) [ 46 ]. Among a selection of 222 CF or CFTR-RD causing variants, 79% were present in the European non-Finnish population, 23% were present in the African population, and 25% were present in the Asian population (19% South Asian, 6% East Asian).…”