Implementation of high resolution whole genome array CGH in the prenatal clinical setting: advantages, challenges, and review of the literature

Abstract

Array Comparative Genomic Hybridization analysis is replacing postnatal chromosomal analysis in cases of intellectual disabilities, and it has been postulated that it might also become the first-tier test in prenatal diagnosis. In this study, array CGH was applied in 64 prenatal samples with whole genome oligonucleotide arrays (BlueGnome, Ltd.) on DNA extracted from chorionic villi, amniotic fluid, foetal blood, and skin samples. Results were confirmed with Fluorescence In Situ Hybridization or Real-Time PCR. Fifty-three cases had normal karyotype and abnormal ultrasound findings, and seven samples had balanced rearrangements, five of which also had ultrasound findings. The value of array CGH in the characterization of previously known aberrations in five samples is also presented. Seventeen out of 64 samples carried copy number alterations giving a detection rate of 26.5%. Ten of these represent benign or variables of unknown significance, giving a diagnostic capacity of the method to be 10.9%. If karyotype is performed the additional diagnostic capacity of the method is 5.1% (3/59). This study indicates the ability of array CGH to identify chromosomal abnormalities which cannot be detected during routine prenatal cytogenetic analysis, therefore increasing the overall detection rate. In addition a thorough review of the literature is presented.

Figure 1

Case 12 showing a copy number gain on the short arm of chromosome 5 inherited from the healthy father and a de novo copy number loss on the long arm of chromosome 15. Representation of the chromosomal and genomic location region on chromosome 15 that has the copy number change in the Database of Genomic Variants. A loss of 2.4 Mb in size, which encompasses several RefSeq genes (shown in brackets); the region is not covered by any CNVs determining that it is not polymorphic.

Figure 2

Case 34 showing a copy number loss on the long arm terminal of chromosome 9. Representation of the chromosomal and genomic location region on chromosome 9 that has the copy number change in the Database of Genomic Variants. A loss of 1.35 Mb in size which encompasses several OMIM genes (shown in brackets) and overlaps with a DECIPHER syndrome (the 9q microdeletion syndrome- shown by the red arrow). The area is not covered by a significant number of CNVs determining that it is not polymorphic.

Figure 3

Case 34 showing a copy number gain on the short arm of chromosome 17. Representation of the chromosomal and genomic location region on chromosome 17 that has the copy number change in the Database of Genomic Variants. A gain of 1.95 Mb in size which encompasses some OMIM genes and overlaps with a DECIPHER syndrome (the Miller-Dieker syndrome—shown by the red arrow). The area is not covered by a significant number of CNVs determining that it is not polymorphic.

Figure 4

FISH analysis showing the confirmation of the unbalanced translocation in Case 34, using subtelomeric probes for chromosomes 9 and 17. Chromosome 8p and q probes (b) are also included in the probe mixture used (VYSIS, ToTelVysion probes). (a) Probes used: subtelomeric 9p and 17q, the top red arrow points at the derivative chromosome 9 (showing the deletion of 9q) and the green arrows point at chromosome 17. (b) Probes used: subtelomeric 17p, 8p and 8q, the red arrow points at the derivative chromosome 9 (showing the duplication of 17p) the green arrows point at chromosome17p.