Validation of a Chromosomal Microarray for Prenatal Diagnosis Using a Prospective Cohort of Pregnancies with Increased Risk for Chromosome Abnormalities.
OBJECTIVE
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 log2ratio 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.


CONCLUSIONS
This chromosomal microarray showed excellent diagnostic performance with improved detection rates compared to karyotyping for prenatal diagnosis of clinically relevant fetal chromosomal abnormalities.
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Dale
D
Wright
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Louise
L
Carey
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Siobhan
S
Battersby
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Thuy
T
Nguyen
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Melanie
M
Clarke
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Benjamin
B
Nash
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Elee
E
Gulesserian
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Jill
J
Cross
Department of Cytogenetics, Sydney Genome Diagnostics, The Children's Hospital at Westmead , Westmead, Australia .
Artur
A
Darmanian
D000782:Aneuploidy; D025063:Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods*; D004314:Down Syndrome / Q000175:diagnosis; D005260:Female; D006801:Humans; D059785:Karyotype; D007621:Karyotyping / Q000379:methods; D009030:Mosaicism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D011296:Prenatal Diagnosis / Q000379:methods*; D011446:Prospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014314:Trisomy / Q000175:diagnosis
chromosome microarray; copy number abnormality; prenatal diagnosis