Validation of a Chromosomal Microarray for Prenatal Diagnosis Using a Prospective Cohort of Pregnancies with Increased Risk for Chromosome Abnormalities.

AIM: Validation of a chromosomal microarray for improved prenatal diagnosis for chromosomal abnormalities among high-risk pregnancies.

METHODS: A cohort of 213 pregnancies was investigated by chromosomal microarray and the results were compared with quantitative fluorescent polymerase chain reaction (QF-PCR), karyotype, and 850K single-nucleotide polymorphism microarray results. The detection limit of mosaicism was determined by assaying different trisomy mosaic constructs down to ∼12%. Imprecision estimates from replicates of mean log2 ratio values for a 200 kb deletion and 400 kb duplication were determined by evaluating the coefficient of variation (CV%).

RESULTS: Excluding pregnancies with aneuploidy, the chromosomal microarray detected 19/213 (8.9%) pregnancies with copy number abnormalities. These were classified as pathogenic in 11/213 (5.2%) cases, as variants of uncertain significance in 4/213 (1.9%) cases, and as likely benign in 4/213 (1.9%) cases. In 15/213 (7.0%) pregnancies, these abnormalities were not detectable by karyotype. Importantly, 8/11 (72.7%) of the pathogenic abnormalities detected by chromosomal microarray were only detectable by this modality. There were no false-positive results and only eight false-negative results. The chromosomal microarray showed excellent sensitivity (96.2%) and specificity (100.0%). The lower detection limit for mosaicism was ∼12%. Imprecision for the 0.2 Mb deletion (11.6 CV%) and 0.4 Mb duplication (5.9 CV%) was very low.

CONCLUSION: This chromosomal microarray showed excellent diagnostic performance with improved detection rates compared to karyotyping for prenatal diagnosis of clinically relevant fetal chromosomal abnormalities.