Lung sensitizing monogenic variant carrier frequency in idiopathic bronchiectasis

Authors

• J Berghout
• AJ Oler
• JB Lack
• W Cao
• E Karlins
• R Ghosh
• BA Siefert
• MN Similuk
• K Kumar
• AJ Lipton
• KP Fennelly
• KN Olivier
• SM Holland
• MA Walkiewicz
• J Yan

Abstract

Bronchiectasis is a persistent inflammation and dilation of lung airways that increases susceptibility to respiratory infection. Patients with cystic fibrosis (CF) disease, primary ciliary dyskinesia, and several other rare genetic conditions develop bronchiectasis as their condition progresses, however it can also present idiopathically. We conducted computational genetic analyses in 299 idiopathic cases to determine the heterozygous carrier frequency of pathogenic variants, focusing on genes where recessive inheritance leads to disease.

All participants were enrolled through the NIAID Centralized Sequencing Program (CSP). Each received a clinical evaluation and exome or genome sequencing with harmonized variant calling. A control cohort was assembled using 765 unrelated, ancestry-matched non-proband CSP participants, excluding families where ascertainment was for bronchiectasis-related conditions. Observed carrier frequencies were compared using a beta binomial posterior model with Markov Chain Monte Carlo draws.

Preliminary results show the idiopathic bronchiectasis cohort is enriched for heterozygous CFTR:p.Phe508del, with this variant observed in 5% of case participants (90% credible interval: 3-8%) compared to 3% (90% CI: 2-4%) of controls, yielding an odds ratio of 2.17 (+/- 1.0). Presence of any pathogenic variant in CFTR aligning to CFTR2 curation had a carrier frequency of 9% (CI: 8-13%) in cases compared to 6% (CI:4-7%) in controls.

These data support the model of idiopathic bronchiectasis being associated with elevated carriage of CFTR pathogenic variants, and ongoing work will determine if this generalizes to include elevated carrier rates in other candidate genes. Together, these may explain a fraction of the etiology and risk for idiopathic cases.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Tuesday, August 6, 2024