Whole-genome array as a first-line cytogenetic test in prenatal diagnosis.

Abstract

The main goal of cytogenetic prenatal diagnosis is to inform prospective parents about the chromosomal status of their fetus. A chromosomal aberration usually causes an abnormal phenotype in childhood. Prenatal whole-genome cytogenetic diagnosis was for a long time dependent on karyotyping, which requires time-consuming cell culturing, has a limited resolution (5–10 Mb) and is dependent on optimal harvesting and chromosome staining conditions. Nowadays, genomic microarray technology allows whole-genome testing at a higher resolution and it can be applied to uncultured fetal material, allowing shorter reporting times when compared with classical cytogenetic techniques. Genomic microarray testing has been recommended for routine postnatal cytogenetics in cases of intellectual disability and/or multiple congenital anomalies1, and for prenatal diagnosis in cases of fetal ultrasound anomalies2. However, its implementation for all indications in prenatal genetic diagnosis is still under discussion3–6. The main arguments against offering prenatal array testing for all indications are the possibility of detecting: (1) CNVs causing well-described clinically significant anomalies not related to the initial indication (unexpected diagnoses); (2) CNVs associated with a variable expressivity and heterogeneity of clinical features, with an as yet unquantifiable chance of an abnormal phenotype if found prenatally (so called susceptibility loci (SL) for neurodevelopmental disorders); and (3) variants of unknown clinical significance (VOUS). Such findings may complicate genetic counseling7–12 and these issues raise further questions, such as which outcomes of genomic microarrays should be reported to pregnant couples? Should they be offered a choice regarding about which possible array outcomes they wish to be informed? Is extensive genetic pretest counseling in every case necessary and feasible in clinical practice? Since this new technology is already present in prenatal clinics, rather than debating whether array testing should be performed for all referrals of invasive cytogenetic prenatal diagnosis, we should instead be discussing how to meet this challenge. In this Editorial, we review the current international status regarding the use of array technology for prenatal diagnosis. We discuss platforms and testing resolution, indications, counseling, (possible problematic) findings and the decision regarding what should be reported to the future parents.