Performance of non-invasive prenatal screening for 15q11q13 copy number variations in a cohort of 90,693 pregnancies

Abstract

Deletions and duplications within the 15q11q13 chromosomal region are associated with Prader-Willi syndrome, Angelman syndrome, and 15q11q13 duplication syndrome. However, prenatal ultrasound findings were unremarkable in the majority of affected fetuses. The aim of this study was to evaluate the efficacy of non-invasive prenatal screening (NIPS) in identifying these syndromes in 90,693 pregnancies within the general population. We retrospectively analyzed 90,693 pregnant women who underwent NIPS at Longgang Maternal and Child Health Hospital in Shenzhen from November 2022 to January 2026. For high-risk 15q11q13 copy number variations (CNVs) identified, we performed chromosomal microarray analysis (CMA) on amniotic fluid, followed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) or further CMA to determine the CNVs’ genetic origin, with subsequent follow-up. NIPS screening identified 4 high-risk cases for 15q11q13 deletion and 7 for duplication. Among the deletion cases, 3 were confirmed by CMA to have a 5–6 Mb deletion (2 maternal, 1 unverified), while 1 declined further testing. For duplication, 6 underwent amniocentesis, with CMA confirming 5 cases (2 maternal, 2 paternal, 1 unverified), 1 normal result, and 1 declined further testing. Of the 8 true-positive cases, 7 had normal ultrasounds, but 1 fetus with duplication exhibited growth retardation. Pregnancy outcomes included 6 terminations, one delivery with paternal duplication showing mild language delay at nearly 2 years, and another with maternal duplication lost to follow-up. NIPS can effectively detect CNVs at the 15q11q13 locus with a high positive predictive value, but its sensitivity, specificity, negative predictive value, and false-negative rate could not be determined in this study due to the lack of confirmatory testing in low-risk cases. Invasive prenatal diagnosis remains essential for validation.