A Novel Non-Invasive Prenatal Sickle Cell Disease Test for All At-Risk Pregnancies - PubMed

A Novel Non-Invasive Prenatal Sickle Cell Disease Test for All At-Risk Pregnancies - PubMed

A Novel Non-Invasive Prenatal Sickle Cell Disease Test for All At-Risk Pregnancies

Julia van Campen 1, Lee Silcock 2, Shu Yau 3, Yvonne Daniel 4, Joo Wook Ahn 1, Caroline Ogilvie 1 5, Kathy Mann 3, Eugene Oteng-Ntim 6 7

Affiliations 

• PMID: 32097993
 
• DOI: 10.1111/bjh.16529

Abstract

Sickle cell disease (SCD) is the most common genetic haematological disorder. The availability of non-invasive prenatal diagnosis (NIPD) is predicted to increase uptake of prenatal diagnosis for SCD, as it has no perceived procedure-related miscarriage risk. We report the development of a targeted massively parallel sequencing (MPS) assay for the NIPD of fetal SCD using fetal cell-free (cf)DNA from maternal plasma, with no requirement for paternal or proband samples. In all, 64 plasma samples from pregnant women were analysed: 42 from SCD carriers, 15 from women with homozygous (Hb SS) SCD and seven from women with compound heterozygous (Hb SC) SCD. Our assay incorporated a relative mutation dosage assay for maternal carriers and a wild type allele detection assay for affected women (Hb SS/Hb SC). Selective analysis of only smaller cfDNA fragments and modifications to DNA fragment hybridisation capture improved diagnostic accuracy. Clinical sensitivity was 100% and clinical specificity was 100%. One sample with a fetal fraction of <4% was correctly called as 'unaffected', but with a discordant genotype (Hb AA rather than Hb AS). Six samples gave inconclusive results, of which two had a fetal fraction of <4%. This study demonstrates that NIPD for SCD is approaching clinical utility.

Keywords: NIPD; cell-free DNA; haematology; massively parallel sequencing; sickle cell disease.

© 2020 British Society for Haematology and John Wiley & Sons Ltd.

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