Affiliation:
1. North Thames Genomic Laboratory Hub Great Ormond Street NHS Foundation Trust London UK
2. Health Economics Group University of Exeter Exeter UK
3. Genetic and Genomic Medicine UCL Great Ormond Street Institute of Child Health London UK
Abstract
AbstractObjectivesTo develop a flexible droplet digital PCR (ddPCR) workflow to perform non‐invasive prenatal diagnosis via relative mutation dosage (RMD) for maternal pathogenic variants with a range of inheritance patterns, and to compare the accuracy of multiple analytical approaches.MethodsCell free DNA (cfDNA) was tested from 124 archived maternal plasma samples: 88 cases for sickle cell disease and 36 for rare Mendelian conditions. Three analytical methods were compared: sequential probability ratio testing (SPRT), Bayesian and z‐score analyses.ResultsThe SPRT, Bayesian and z‐score analyses performed similarly well with correct prediction rates of 96%, 97% and 98%, respectively. However, there were high rates of inconclusive results for each cohort, particularly for z‐score analysis which was 31% overall. Two samples were incorrectly classified by all three analytical methods; a false negative result predicted for a fetus affected with sickle cell disease and a false positive result predicting the presence of an X‐linked IDS variant in an unaffected fetus.ConclusionsddPCR can be applied to RMD for diverse conditions and inheritance patterns, but all methods carry a small risk of erroneous results. Further evaluation is required both to reduce the rate of inconclusive results and explore discordant results in more detail.
Funder
National Institute for Health and Care Research
Subject
Genetics (clinical),Obstetrics and Gynecology
Cited by
5 articles.
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