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Laboratory Testing of CFTR Gene in Light of Evolving Professional Guidelines and Standards for Carrier Screening– A Reference Laboratory’s Experience 

Health Services and Implementation
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene is one of the most well-characterized and clinically tested Mendelian genes. To date (September 2024), there are 1,167 variants annotated on the CFTR2 website, of which 1,085 are CF-causing, compared to 382 CF-causing variants reported back in September 2021. As more CFTR variants are being discovered and characterized, and genomic techniques for variant detection have rapidly evolved, professional guidelines related to CF carrier screening have also been updated. Of importance, ACMG has provided recommendations for carrier screening when using a defined variant panel from assessing for a minimum of 23 CF-causing variants to an expanded panel with minimum of 100 CFTR variants. This updated recommendation assists clinical laboratories with modernizing CFTR carrier testing by ensuring improved clinical sensitivity for pan-ethnic screening populations. ARUP Laboratories, a national reference laboratory, performs CF diagnostic and CF carrier screening for patients with diverse ethnicity backgrounds using several molecular tests, including a 165-variant CFTR panel. In this study, we retrospectively reviewed and summarized our clinical observations from the 165-variant panel testing, in light of the evolving professional standards and guidelines of CF carrier testing.



 

Methods:
A cohort of clinically tested patients (n=212,342) using a 165-variant CFTR panel was retrospectively analyzed for testing indications, ethnicity distribution, and CFTR variant detection rate.

Results:
In this patient cohort, 77.7% and 24% of the patients were reported to have “No” or “Unknown” CF symptoms, indicating for known or possible carrier testing indications (for patients of or over 13 years). CF symptoms of “Yes”, or diagnostic testing, was reported for 0.13% of all patients. Among the patients with ethnicity information reported (75% of all patients), White (33.5%), Asian (11.3%), Hispanic (13.2%), and multiethnic backgrounds (8.61%) are the top 4 ethnicity groups. The overall CFTR variant detection rate is 1.67% among all 424,684 CFTR alleles tested in this cohort. Detection rate of the individual panel variants ranges from 3,887 alleles for p.Phe508del (0.92%) to 10 alleles or less (≤0.002%) for the majority (>100 variants out of 165 variants) of the CFTR variants on the panel. In addition to p.Phe508del, the most detected CFTR variant by the 165-variant panel are p.Arg117His, p.Gly542X, p.Leu206Trp, p.Gly551Asp, p.Leu967Ser, p.Asn1303Lys, p.Trp1282X, p.Phe312del, and p.Arg553X. Of these variants, the p.Leu206Trp was not in the previous ACMG 23-variant list, but was recently added to the ACMG 100-variant panel. Interestingly, 6 of the top 30 detected variants in our patients were not included on the new ACMG 100-variant list. These variants were detected at a rate of 0.27-0.005%, or 114 to 23 CFTR alleles, in this patient cohort. ARUP’s 165-variant CFTR panel includes all 23 variants from ACMG’s “core” panel, and 69 variants on the updated ACMG 100-variant panel.

Conclusion:
Selecting CF-causing variants for carrier testing via a targeted variant panel depends on several factors including, but not limited to, the pathogenicity of the variants, prevalence of variants in the targeted testing population, and the cost effectiveness of the assay with increasing clinical sensitivity when more rare variants are included in the panel. The present study provides clinical observations of a 165 CFTR variant panel in a large cohort of patients. Our experience can be useful for laboratories considering updating their targeted panels. If resource for continuing updating CFTR carrier testing using a targeted genotyping approach is also a constraint, laboratories might consider to plan to adopt an NGS-based, full-gene sequencing strategy for CFTR carrier testing, as to prepare for transitioning to a more comprehensive, multi-gene carrier screen of additional autosomal recessive and X-linked conditions defined by ACMG 2021 Practice Resource in this regard.

Agenda

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