Sequencing as a first-line methodology for cystic fibrosis carrier screening

Kyle A Beauchamp,Katherine A Johansen Taber,Peter V Grauman,Lindsay Spurka,Jeraldine Lim-Harashima,Ashley Svenson,James D Goldberg,Dale Muzzey

doi:10.1038/s41436-019-0525-y

Kyle A Beauchamp, Katherine A Johansen Taber + Show 6 more

Open Access

https://doi.org/10.1038/s41436-019-0525-y

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Abstract

PurposeMedical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility. MethodsAnalytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants (“CF23”), sequencing all coding bases in CFTR (“NGS”), and sequencing with large copy-number variant (CNV) identification(“NGS + CNV”). Clinical utility was determined via self-reported actions of at-risk couples (ARCs). ResultsAnalytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant. ConclusionModern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.

Highlights

Cystic fibrosis (CF) is a serious hereditary condition affecting nearly 35,000 individuals in the United States.[1]
Most at-risk couples (ARCs) (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant
In 2001, 25 pathogenic variants were recommended by the American College of Medical Genetics and Genomics (ACMG) for population screening based on their frequency in the general population;[6] a 2004 ACMG revision trimmed this list to focus on 23 common variants with confirmed pathogenicity.[7]

Summary

Introduction

Cystic fibrosis (CF) is a serious hereditary condition affecting nearly 35,000 individuals in the United States.[1]. As the most common life-threatening AR condition in nonHispanic whites,[4] CF is the subject of well-established carrier screening guidelines that predate the completion of the Human Genome Project. In the mid-1990s, the National Institutes of Health began work to develop screening guidelines.[5] In 2001, 25 pathogenic variants were recommended by the American College of Medical Genetics and Genomics (ACMG) for population screening based on their frequency in the general population;[6] a 2004 ACMG revision trimmed this list to focus on 23 common variants with confirmed pathogenicity.[7] Recent American College of Obstetricians and Gynecologists (ACOG) guideline updates have reaffirmed the primacy of these 23 variants.[4]

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