Prevalence of high-penetrant copy number variants in 7734 low-risk pregnancies

The rate of clinically significant copy number variants in chromosomal microarray analysis in low-risk pregnancies is approximately 1%. However, these results include copy number variants with low and variable penetrance, although some patients might be interested only in the detection of high-penetrant variants.

This study aimed to calculate the prevalence of high-penetrant copy number variants in a large cohort of low-risk pregnancies.

This retrospective study was performed using microarray results of pregnancies with normal ultrasound and maternal serum screening. All clinically significant (pathogenic and likely pathogenic) copy number variants were recorded. Of these, only high-penetrant findings were selected. Findings with low and medium penetrance and copy number variants with unknown clinical penetrance, including uniparental disomy of segments not related to known imprinted syndromes, mosaic aneuploidy of <50%, and segmental mosaicism, were excluded. The calculation was performed for the overall cohort, for women aged >35 years and women aged <35 years, and after omission of noninvasive prenatal screening theoretically detectable findings (trisomies 13, 18, and 21).

Clinically significant copy number variants were detected in 118 of 7734 cases (1.50% or 1:65), and high-penetrant copy number variants were detected in 33 of 7734 cases (0.43% or 1:234). In women aged ≥35 years, the rates of high-penetrant copy number variants were 29 of 5734 cases (0.51% or 1:198) and 4 of 2000 cases (0.20% or 1:500) in women aged <35 years (P=.0747). Following the omission of 12 theoretically noninvasive prenatal screening-detectable findings, the rates of high-penetrant copy number variants declined to 21 of 7722 cases (0.27% or 1:368) in the whole cohort-18 of 5723 cases (0.31% or 1:318) in woman aged ≥35 years and 3 of 1999 cases (0.15% or 1:666) in younger women (P=.319).

The risk of high-penetrant copy number variants in low-risk pregnancies exceeds the risk of miscarriage after invasive testing, even after normal noninvasive prenatal screening results. These results are of importance to genetic counselors and obstetricians, to facilitate maternal informed decision-making when considering invasive prenatal testing in low-risk pregnancies.