Prevalence of CFTR variants in PID patients with bronchiectasis - an important modifying co-factor

Background

Cystic fibrosis (CF) is one of the most common life limiting autosomal recessive disorders and is caused by genetic defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID).

Objective

We hypothesized that a ‘carrier’ CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID.

Methods

A within-cohort and population level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed.

Results

Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage, compared to PID patients without the structural lung damage. We identified three additional biallelic cases including several variants not traditionally considered as CF-causing.

Conclusion

Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomics services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders.