Non‐invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis

Abstract

ObjectivesWe aim to develop non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF) and determine costs and implications for implementation.MethodsA next-generation sequencing assay was developed to detect ten common CF mutations for exclusion of the paternal mutation in maternal plasma. Using uptake data from a study exploring views on NIPD for CF, total test-related costs were estimated for the current care pathway and compared with those incorporating NIPD.ResultsThe assay reliably predicted mutation status in all control and maternal plasma samples. Of carrier or affected adults with CF (n = 142) surveyed, only 43.5% reported willingness to have invasive testing for CF with 94.4% saying they would have NIPD. Using these potential uptake data, the incremental costs of NIPD over invasive testing per 100 pregnancies at risk of CF are £9025 for paternal mutation exclusion, and £26 510 for direct diagnosis.ConclusionsWe have developed NIPD for risk stratification in around a third of CF families. There are economic implications due to potential increased test demand to inform postnatal management rather than to inform decisions around termination of an affected pregnancy. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Non‐invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies by relative haplotype dosage

“…Fetal sexing and RhD typing using cffDNA are now in routine clinical service, while aneuploidy screening has been developed by several US‐based companies and is now rapidly being introduced in public health services as well . In the UK, bespoke NIPD tests for exclusion of paternally inherited and de novo mutations have recently been developed through the RAPID project and are now offered as a clinical service . Although technically possible, little attention has been given to NIPD of SGDs, mostly due to the limited number of patients who would request it and the prohibitively high‐testing costs .…”

A Broad Test Based on Fluorescent-Multiplex PCR for Noninvasive Prenatal Diagnosis of Cystic Fibrosis

“…Previous studies were performed on small sample groups and on targeted mutation of the CFTR gene [7,9,10,[16][17][18][19][20]. In contrast, here we analyzed more than 14 samples from high-risk CF pregnancies and over 16 samples from pregnancies with a priori CF risk based on ultrasound findings, the latter secondarily excluded following parental genotyping.…”

“…Therefore, high-sensitivity technology is required to accurately detect it. Recent technological breakthroughs such as next-generation sequencing, microarrays, and droplet digital PCR have enabled the development of NIPD tests for single-gene disorders [3,7,8]. However, technologies for monogenic diseases are still at the experimental laboratory stage mostly due to the limited number of patients who would request it and the prohibitively high testing costs.…”

Recent advances in prenatal genetic screening and testing

“…When Lo et al discovered in 1997 that male fetal DNA could be amplified by PCR from maternal plasma 32 , attention shifted to the analysis of cffDNA from maternal plasma. Initially, PCR-based assays to identify fetal gender 33 , fetal Rhesus genotype 34– 39 , and mutations that cause paternally inherited or de novo single-gene disorders were developed, which is an ongoing field of active investigation 40– 44 . In 2008, two groups reported that shotgun NGS of cell-free DNA (cfDNA) from maternal plasma, of which about 10% originates from the placenta and represents the fetal genome, can be used to determine if there is fetal aneuploidy by counting sequence tags mapped to each chromosome 45, 46 .…”