Highlights
- •Full-gene CFTR sequencing identifies CF-causing genotypes in almost all individuals with CF.
- •Full-gene sequencing can identify gene rearrangements that are often missed by other technologies.
- •The presence of additional variants beyond the causal genotype may affect phenotype or drug response.
- •Full- gene sequencing provides a comprehensive catalog of CFTR variation for each individual.
- •An individual’s full CFTR sequence can be re-analyzed as new tools become available.
Abstract
Background
Cystic fibrosis (CF) is a recessive condition caused by variants in each CF transmembrane
conductance regulator (CFTR) allele. Clinically affected individuals without two identified causal variants typically
have no further interrogation of CFTR beyond examination of coding regions, but the development of variant-specific CFTR-targeted
treatments necessitates complete understanding of CFTR genotype.
Methods
Whole genome sequences were analyzed on 5,058 individuals with CF. We focused on the
full CFTR gene sequence and identified disease-causing variants in three phases: screening
for known and structural variants; discovery of novel loss-of-function variants; and
investigation of remaining variants.
Results
All variants identified in the first two phases and coding region variants found in
the third phase were interpreted according to CFTR2 or ACMG criteria (n = 371; 16 [4.3%] previously unreported). Full gene sequencing enabled delineation
of 18 structural variants (large insertions or deletions), of which two were novel.
Additional CFTR variants of uncertain effect were found in 76 F508del homozygotes and in 21 individuals
with other combinations of CF-causing variants. Both causative variants were identified
in 98.1% (n = 4,960) of subjects, an increase of 2.3 percentage points from the 95.8% (n = 4,847) who had a registry- or chart-reported disease-causing CFTR genotype. Of the remaining 98 individuals, 78 carried one variant that has been associated
with CF (CF-causing [n = 70] or resulting in varying clinical consequences n = 8]).
Conclusions
Complete CFTR gene sequencing in 5,058 individuals with CF identified at least one DNA variant
in 99.6% of the cohort that is targetable by current molecular or emerging gene-based
therapeutic technologies.
Keywords
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Article info
Publication history
Published online: November 12, 2021
Accepted:
October 29,
2021
Received in revised form:
October 27,
2021
Received:
July 23,
2021
Identification
Copyright
© 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
