Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies

TLDR

Prenatal testing has not reached consensus on using chromosomal microarray analysis, leading to adoption of alternatives such as Prenatal BACs‑on‑Beads. The study aimed to determine the frequencies of submicroscopic defects detectable by PNBoBs across various prenatal indications using 9,648 prospectively analyzed samples. The authors calculated frequencies and 95 % confidence intervals of genomic defects per indication, finding an overall incidence of 0.7 %. The study found that cryptic imbalances were most often in the DiGeorge syndrome critical region, with an overall incidence of 0.7 %, a diagnostic yield of 1 in 298 in low‑risk pregnancies, prevalences of 1/992 and 1/850 for DGS microdeletion and microduplication, a constant a priori risk of ~0.3 %, a higher‑than‑expected 22q11.2 microdeletion rate independent of maternal age, and implications for cell‑free DNA screening and prenatal 22q11 deletion testing.

Abstract

The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs-on-Beads(TM) (PNBoBs(TM) ) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBs(TM) under different prenatal indications.A total of 9648 prenatal samples were prospectively analyzed by karyotyping plus PNBoBs(TM) and classified by prenatal indication. The frequencies of the genomic defects and their 95%CIs were calculated for each indication.The overall incidence of cryptic imbalances was 0.7%. The majority involved the DiGeorge syndrome critical region (DGS). The additional diagnostic yield of PNBoBs(TM) in the population with a low a priori risk was 1/298. The prevalences of DGS microdeletion and microduplication in the low-risk population were 1/992 and 1/850, respectively.The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell-free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis.