Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases

Abstract

Objective: To evaluate the use of array comparative genomic hybridization (aCGH) for prenatal diagnosis, including assessment of variants of uncertain significance, and the ability to detect abnormalities not detected by karyotype, and vice versa.

Methods: Women undergoing amniocentesis or chorionic villus sampling (CVS) for karyotype were offered aCGH analysis using a targeted microarray. Parental samples were obtained concurrently to exclude maternal cell contamination and determine if copy number variants (CNVs) were de novo, or inherited prior to issuing a report.

Results: We analyzed 300 samples, most were amniotic fluid (82%) and CVS (17%). The most common indications were advanced maternal age (N=123) and abnormal ultrasound findings (N=84). We detected 58 CNVs (19.3%). Of these, 40 (13.3%) were interpreted as likely benign, 15 (5.0%) were of defined pathological significance, while 3 (1.0%) were of uncertain clinical significance. For seven (approximately 2.3% or 1/43), aCGH contributed important new information. For two of these (1% or approximately 1/150), the abnormality would not have been detected without aCGH analysis.

Conclusion: Although aCGH-detected benign inherited variants in 13.3% of cases, these did not present major counseling difficulties, and the procedure is an improved diagnostic tool for prenatal detection of chromosomal abnormalities.

Figure 1

Copy number losses of uncertain clinical significance. (A) BAC aCGH result on a fetal sample, showing de novo copy number loss of one BAC clone in Xq27.3 (Table 3 case no. 7). Normalized data from both dye-reversal hybridizations are shown on the left in red and blue and combined data are shown on the right in green. The red circles indicate the clone affected by copy number loss. (B) Top panel: Oligo aCGH result showing two deleted clones in 15q26 (Table 3 case no. 11) (indicated by the red circle); middle panel: FISH results on metaphase spreads with the deleted clones; bottom panel: schematic of the genomic region from the Ensembl genome browser showing gene content of the deletion (red square)