Diversity ofCFTRvariants across ancestries characterized using 454,727 UK biobank whole exome sequences

Abstract

Limited understanding of the diversity of CFTR variants across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Characterizing the distribution of CFTR variants across ancestries is, therefore, critical for revolutionizing molecular diagnoses of CF. By interrogating 454,727 UK biobank whole exome Sequences, we detected over 4,000 CFTR variants, including novel ancestry-specific variants, across six ancestries. F508del was the most prevalent CF-causing variant found across the ancestries, except in East Asia, where V520F was the most prevalent. Sixteen participants had two CF-causing variants, with two diagnosed as CF. We found 154 participants with a CF-causing and varying clinical consequences (VCC) variant. Overall, participants with multiple clinically relevant variants reported indications significantly associated with CF and its pulmonary phenotypes [Bonferroni adjusted p<0.05]. Potentially, participants with classical CF phenotypes may benefit from current CF therapies.

In VitroModulator Responsiveness of 655CFTRVariants Found in People With CF

“…Cystic fibrosis (CF) is a progressive autosomal recessive condition affecting over 40.000 people in the United Stated and over 100.000 people worldwide. CF is caused by specific variants 1 of the CFTR gene that result, through various mechanisms, in a dysfunctional CFTR protein. More than 4000 CFTR variants have been reported, including over 1000 exonic variants (www.genet.sickkids.on.ca, Ideozu+, 2023 [1]), but not all cause disease.…”

“…CF is caused by specific variants 1 of the CFTR gene that result, through various mechanisms, in a dysfunctional CFTR protein. More than 4000 CFTR variants have been reported, including over 1000 exonic variants (www.genet.sickkids.on.ca, Ideozu+, 2023 [1]), but not all cause disease. To date, 1654 variants have been reported in pwCF to the Clinical and Functional Translation of CFTR (CFTR2) project (https://cftr2.org).…”