How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings?

OBJECTIVE

Chromosomal Microarray Analysis (CMA) has a higher detection rate of pathogenic chromosome abnormalities over conventional (G-band) karyotyping. The optimum resolution of CMA in the prenatal setting remains debatable. Our objective was to determine if an increased detection rate was obtained by performing differing resolution of CMA on the same fetal samples and whether this resulted in an increase in variants of uncertain clinical significance (VOUS).

METHODS

Sixty-two fetal cases initially underwent a 1 Mb targeted BAC microarray within a clinical diagnostic setting in addition to conventional karyotyping. At the conclusion of pregnancy, a higher resolution 60 K oligonucleotide microarray was performed.

RESULTS

The 1 Mb BAC analysis demonstrated a detection rate of pathogenic copy number variations (CNVs) in 4.1% (95% CI 2.1-7.6) of cases and a variation of unknown significance (VOUS) rate of 0.4% (95% CI 0.07-2.2) over conventional G-band karyotyping. The 60 K array had an additional pathogenic detection rate of 4.8% (95% CI 1.6-13.3) over the BAC array but also detected an additional 8% (95% CI 1.3-14.8) VOUS.

CONCLUSION

As the CMA platform resolution increases detection rates increase but are associated with an increase in VOUS rates. Our findings support the need for further large scale studies to inform the national consensus on the resolution required and on reporting of VOUS in the antenatal setting.