Analysis of the Genome Aggregation Database (gnomAD) reveals a global burden of cystic fibrosis and the need for improved diagnosis and care

Abstract

Background: The presence of cystic fibrosis (CF) in diverse groups is known but its incidence is not established in non-European populations. We predict that the number of births with CF in populations with non-European and European ancestry are comparable, and that sampling the general population may inform improved diagnostic and therapeutic strategies.

Methods: We curated pathogenic CFTR variants from the Genome Aggregation Database (gnomAD, versions 2.1 and 4.0) for different groups and estimated the incidence per 100,000 births using Hardy-Weinberg equilibrium. To estimate annual births with CF, we used United Nations population statistics. Additionally, we estimated the percentages of alleles missed by common screening panels and those not approved for treatment using highly effective modulator therapies (HEMT).

Findings: CF affects 44-52, 11-14, 7, 6, 4, and 0.2-1 births per 100,000 in European, African/African American, Admixed American, South Asian, East Asian, and Middle Eastern groups, respectively. Due to higher birth rates, the estimated annual births with CF in India (1426-1582) and Brazil (330-390) are comparable to those in the US (∼1000) and UK (∼300). The expanded Wisconsin screening panel misses the fewest variants in all groups (1-30% pathogenic alleles), while other screening panels miss 25->70% of pathogenic alleles from non-European groups. Of the pathogenic alleles in non-European groups, 25-40% were not approved for treatment using HEMT.

Interpretation: Absolute number of CF births in South America, Asia, and Africa may be comparable to those in the US and Europe. Improved diagnostics, therapeutics, and access to HEMT will benefit thousands of people with CF globally.

Funding: None.

Keywords: Cystic fibrosis; Diagnosis of CF; Genetic epidemiology of cystic fibrosis; Treatment of CF.