The clinical utility of sequencing the entirety of CFTR

Molly B Sheridan; Melis A Aksit; Kymberleigh Pagel; Kurt Hetrick; Hannah Shultz-Lutwyche; Ben Myers; Kati J Buckingham; Rhonda G Pace; Hua Ling; Elizabeth Pugh; Wanda K O'Neal; Michael J Bamshad; Ronald L Gibson; Michael R Knowles; Scott M Blackman; Garry R Cutting; Karen S Raraigh

doi:10.1016/j.jcf.2024.04.018

The clinical utility of sequencing the entirety of CFTR

J Cyst Fibros. 2024 May 10:S1569-1993(24)00062-6. doi: 10.1016/j.jcf.2024.04.018. Online ahead of print.

Authors

Molly B Sheridan¹, Melis A Aksit¹, Kymberleigh Pagel², Kurt Hetrick¹, Hannah Shultz-Lutwyche¹, Ben Myers¹, Kati J Buckingham³, Rhonda G Pace⁴, Hua Ling¹, Elizabeth Pugh¹, Wanda K O'Neal⁴, Michael J Bamshad⁵, Ronald L Gibson⁶, Michael R Knowles⁴, Scott M Blackman⁷, Garry R Cutting¹, Karen S Raraigh⁸

Affiliations

¹ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² The Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁴ Department of Medicine, Marsico Lung Institute/UNC CF Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA.
⁶ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
⁷ Division of Pediatric Endocrinology and Diabetes, Johns Hopkins University, Baltimore, MD 21287, USA.
⁸ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: kraraigh@jhmi.edu.

PMID: 38734509
DOI: 10.1016/j.jcf.2024.04.018

Abstract

Background: Cystic fibrosis (CF) is caused by deleterious variants in each CFTR gene. We investigated the utility of whole-gene CFTR sequencing when fewer than two pathogenic or likely pathogenic (P/LP) variants were detected by conventional testing (sequencing of exons and flanking introns) of CFTR.

Methods: Individuals with features of CF and a CF-diagnostic sweat chloride concentration with zero or one P/LP variants identified by conventional testing enrolled in the CF Mutation Analysis Program (MAP) underwent whole-gene CFTR sequencing. Replication was performed on individuals enrolled in the CF Genome Project (CFGP), followed by phenotype review and interrogation of other genes.

Results: Whole-gene sequencing identified a second P/LP variant in 20/43 MAP enrollees (47 %) and 10/22 CFGP enrollees (45 %) who had one P/LP variant after conventional testing. No P/LP variants were detected when conventional testing was negative (MAP: n = 43; CFGP: n = 13). Genome-wide analysis was unable to find an alternative etiology in CFGP participants with fewer than two P/LP CFTR variants and CF could not be confirmed in 91 % following phenotype re-review.

Conclusions: Whole-gene CFTR analysis is beneficial in individuals with one previously-identified P/LP variant and a CF-diagnostic sweat chloride. Negative conventional CFTR testing indicates that the phenotype should be re-evaluated.

Keywords: CFTR; Cystic fibrosis; Genetic testing; Genome sequencing; Whole-gene sequencing.