Clinical Utility of Noninvasive Prenatal Screening for Rare Chromosome
Abnormalities in Singleton Pregnancies
Abstract
Objective: To systematically investigate the clinical utility of
noninvasive prenatal screening (NIPS) commercially used for the common
fetal aneuploidies as a prenatal screening tool for rare chromosome
abnormalities (RCAs). Design: Prospective study. Setting:
Hospital-based. Population or Sample: 528 gravidas with positive NIPS
results for RCAs. Methods: Gravidas with positive NIPS results for RCAs
subsequently underwent amniocentesis for single nucleotide polymorphism
array (SNP-array) were recruit. The degrees of concordance between NIPS
and SNP-array were classified into full concordance, partial
concordance, discordance related and discordance. Main Outcome Measures:
The positive predictive values (PPVs) for rare aneuploidies and
segmental imbalances, while incidental findings for regions of
homozygosity/uniparental disomy (ROH/UPD), were used to evaluate the
performance of NIPS. Results: Of the 528 gravidas with positive NIPS
results, 29.2% were confirmed with positive prenatal SNP-array results
(154/528). The PPVs for rare aneuploidies and segmental imbalances were
6.1% (7/115) and 21.1% (87/413), respectively. ROH/UPDs, as incidental
findings, have been identified in 9.5% (50/528) of gravidas with
positive NIPS results. The PPV for clinical significant findings was
8.9% (47/528), including 7 cases with mosaic rare aneuploidies, 35 with
pathogenic/likely pathogenic copy number variants, and 5 with imprinting
disorders. Conclusions: NIPS commercially used for the common fetal
aneuploidies yielded low PPV for rare aneuploidies, moderate PPV for
segmental imbalances, and incidental findings for ROH/UPD. For the low
PPV for clinical significant findings, NIPS has limited clinical utility
for RCAs. Prenatal SNP-array should be regarded as the first-tier test
for positive NIPS, particularly for those involved imprinted
chromosomes.