Prevalence of high-penetrant copy number variants in 7,734 low-risk pregnancies

Background : The rate of clinically significant copy number variants (CNVs) in chromosomal microarray analysis in low-risk pregnancies is about 1%. However, these results include CNVs with low and variable penetrance, while some patients might be interested only in detection of high-penetrant variants. Objective : To calculate the prevalence of high-penetrant CNVs in a large cohort of low-risk pregnancies. Study design : This retrospective study was performed using microarray results of pregnancies with normal ultrasound and maternal serum screening. All clinically significant (pathogenic and likely pathogenic) CNVs were recorded. Of these, only high-penetrant findings were selected. We excluded findings with low and medium penetrance, as well as CNVs with unknown clinical penetrance including: uniparental disomy of segments not related to known imprinted syndromes, mosaic aneuploidy of lower than 50%, and segmental mosaicism. The calculation was performed for the overall cohort, for women older and younger than 35 years, and after omission of non-invasive prenatal screening (NIPS) theoretically detectable findings (trisomies 13, 18 and 21). Results : Clinically significant CNVs were detected in 118/7734 of cases (1:65, or 1.5%), and high-penetrant CNVs - in 33/7734 of cases (1:234, or 0.43%). In woman aged ≥35 years the rate of high-penetrant CNVs was 29/5734 (1:198, or 0.51%), vs. 4/2000 in woman aged<35 years (1:500, or 0.20%), p=0.0747. Following omission of 12 theoretically NIPS-detectable findings, the rate of high-penetrant CNVs declined to 21/7722 (0.27% or 1:368) in the whole cohort – 18/5723 (0.31% or 1:318) in woman aged ≥35 years, vs. 3/1999 (0.15% or 1:666) in younger women, p=0.319. Conclusion : The risk for high-penetrant CNVs in low-risk pregnancies exceeds the risk for miscarriage following invasive testing, even after normal NIPS 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.