Parent-of-origin testing of prenatal copy number variations: a retrospective study of 167 family cases

Abstract

Low-penetrance pathogenic copy number variations (CNVs), variation of uncertain significance (VUS) CNVs and likely pathogenic CNVs present a challenge for prenatal diagnosis. Previous studies have clarified the influence of a parent-of-origin test on the prenatal VUS CNVs. However, the influence of parent-of-origin tests on prenatal likely pathogenic (LP) or low-penetrance pathogenic CNVs (pCNVs) have not been evaluated. Here, among 2273 pregnant women undergoing prenatal diagnosis, 236 CNVs were reported by chromosomal microarray analysis (CMA) including 69 full-penetrance pCNVs, 44 low-penetrance pCNVs, 113 VUS CNVs and 10 LP CNVs. Based on the subsequent parent-of-origin tests, CNVs were classified as de novo, inherited and unknown group. Firstly, a total of 112 couple (62 VUS CNVs, two LP CNVs and 48 pCNVs) chose parent-of-origin tests and 88 inherited CNVs (51 VUS CNVs, two LP CNVs and 35 pCNVs ) were identified. Then, the effect of parent-of-origin tests was focused on 44 low-penetrance pCNVs, 113 VUS CNVs and 10 LP CNVs in this study (n = 167). For 44 low-penetrance pCNVs, termination of pregnancy (TOP) rates in de novo, inherited and unknown group were 100% (5/5), 23.5% (4/17) and 40.9% (9/22), respectively. TOP decisions in low-penetrance pCNVs were mainly affected by de novo and abnormal ultrasound findings. For 113 VUS CNVs, inherited VUS CNVs dramatically reduced anxiety reflected by TOP rates in de novo (18.2%, 2/11), inherited (0/51) and unknown group (2.0%, 1/51). Notably, prenatal minor structural defects often disappeared after birth. These results suggested the majority VUS CNVs have no appreciable pathogenicity. For 10 LP CNVs, TOP rates in inherited and unknown group were 0% (0/2) and 87.5% (7/8), which suggested that it is imperative that parent-of-origin tests be offered for LP CNVs to bring the classification to pathogenic or VUS.

Keywords: Copy number variations; Likely pathogenicity; Low-penetrance pathogenicity; Parent-of-origin test; Variation of uncertain significance.

Fig. 1

The distribution of 236 CNVs.

Fig. 2

The influence of parent-of-origin tests on pregnant decisions and outcomes in fetuses with low-penetrance pCNVs. Based on parent-of-origin tests, the cases number in de novo, inherited and unknown group was 5, 17 and 22, respectively. The total TOP rate among low-penetrance pCNVs was 40.9% (18/44). The TOP rates of de novo, inherited and unknown group were 100%, 23.5% and 40.9%, respectively. Among 26 cases with continued pregnancy, two times follow-up were performed.

Fig. 3

The influence of parent-of-origin tests on pregnant decisions and outcomes in fetuses with VUS CNVs. Based on parent-of-origin tests, the cases number in de novo, inherited and unknown group was 11, 51 and 51, respectively. The total TOP rate of VUS CNVs cases was 2.7% (3/113). The TOP rates of de novo, inherited and unknown group were 18.2%, 0% and 2%, respectively. Among 110 cases with continued pregnancy, routine follow-up was performed. The abnormal pregnancy outcomes in the de novo, inherited and unknown group were listed.

Fig. 4

The influence of parent-of-origin tests on pregnant decisions and outcomes in fetuses with LP CNVs. Based on parent-of-origin tests, the cases number in de novo, inherited and unknown group was 0, 2 and 8, respectively. The total TOP rate of LP CNVs cases was 70% (7/10). The TOP rates in inherited and unknown group were 0% and 87.5%, respectively. Among eight cases with continued pregnancy, routine follow-up was performed. The abnormal pregnancy outcomes in inherited and unknown group were listed.