Clinical experience with non-invasive prenatal screening for single-gene disorders (NIPT-SGD).

OBJECTIVES To assess the performance of a non-invasive screening test for a panel of dominant disorders with a combined population incidence of 1 in 600. The panel included 30 genes covering 25 disorders including Noonan spectrum disorders (NSDs), skeletal disorders, craniosynostosis syndromes, Cornelia de Lange syndrome (CdLS), Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1 related intellectual disability, CHARGE syndrome, Sotos syndrome and Rett syndrome. METHODS Cell-free fetal DNA isolated from maternal plasma samples accessioned from April 14, 2017, to November 27, 2019, was analyzed by next generation sequencing, targeting 30 genes, to look for pathogenic or likely pathogenic variants implicated in 25 dominant disease conditions. Testing was offered for women with singleton pregnancies at 9 weeks gestational age or later, with testing on maternal and paternal genomic DNA to assist in interpretation. A minimum 4.5% fetal fraction was required for test interpretation. Variants identified in the mother were deemed inconclusive with respect to fetal carrier status. Confirmatory prenatal or postnatal diagnostic testing was recommended for all screen-positive patients and follow-up information was requested. RESULTS Results were available for 2,208 women, 125 (5.7%) of which were positive. Elevated test-positive rates were found for referrals with a family history of a disorder on the panel, 20/132 (15.2%); a primary indication of fetal long bone abnormality 60/178 (33.7%); fetal craniofacial abnormalities, 6/21 (28.6%); fetal lymphatic abnormalities 20/150 (13.3%) and major fetal cardiac defects 4/31 (12.9%). For paternal age ≥40 years as a sole risk factor, the test positive rate was 2/912 (0.2%). Of the 125 positive cases, follow-up information was available for 65 (52%) with none classified as false-positive. No false-negative cases were identified. CONCLUSIONS Non-invasive prenatal testing can assist in the early detection of a set of single gene disorders, particularly when either abnormal ultrasound findings or a family history is present. Additional clinical studies are needed. NIPT-SGD offers a safe and early prenatal screening option. This article is protected by copyright. All rights reserved.