Identification of submicroscopic chromosomal aberrations in fetuses with increased nuchal translucency and apparently normal karyotype

Objective Fetal nuchal translucency (NT) is assessed by ultrasonography as a screening tool for aneuploidy at 11 to 13 + 6 weeks' gestation. Fetuses with increased NT but apparently normal karyotype are still at higher risk of structural abnormality and a range of genetic syndromes, which may be related to major and submicroscopic chromosomal abnormalities. The aim of this study was to report the prevalence of submicroscopic chromosomal abnormalities in a cohort of apparently euploid fetuses that presented with increased NT. Methods DNA was extracted from stored chorionic villus samples from fetuses found to have increased NT (> 3.5 mm) during first-trimester screening. These samples were examined by microarray-based comparative genomic hybridization (aCGH) using a 44K oligonucleotide array specifically constructed for prenatal screening. Variations in copy number (CNVs) were reported after excluding known non-pathogenic variants and after validation with multiplex ligation-dependent probe amplification (MLPA) or real-time quantitative polymerase chain reaction (qPCR). The prevalence of pathogenic CNVs is reported and the association with NT and other ultrasound findings described. Results CNVs were reported in 6/48 (12.5%) cases by aCGH and the microdeletions or microduplications ranged from 1.1 to 7.9 Mb. Five of these were validated by MLPA/real-time qPCR and four (8.3%) were considered to be pathogenic and clinically significant. The incidence of pathogenic CNVs was 20.0% (2/10) among those cases with other sonographic anomalies and 5.3% (2/38) among those without. Conclusion aCGH allows detection of submicroscopic chromosomal abnormalities, the prevalence of which may be increased in fetuses with NT > 3.5 mm and an apparently normal karyotype.