LAUSR

BACKGROUND Chromosomal microarray analysis (CMA) detects clinically significant copy number variants (CNVs) in about 1% of low-risk pregnancies. As the constantly growing wide use of non-invasive prenatal screening (NIPS) facilitates the detection of chromosomal aberrations, defining the rate of abnormal CMA findings following normal NIPS is of importance for informed decisions regarding prenatal testing and screening options. OBJECTIVE To calculate the residual risk for clinically significant CNVs following theoretically normal NIPS. STUDY DESIGN CMA results of all pregnancies undergoing amniocentesis between the years 2013-2021 in large hospital-based laboratory were collected. Pregnancies with sonographic anomalies, abnormal maternal serum screening or multiple fetuses were excluded. Clinically significant (pathogenic and likely pathogenic) CNVs were divided into: 3-NIPS-detectable (trisomies 13, 18 and 21), 5-NIPS-detectable (including sex chromosome aberrations), 5-NIPS and common microdeletion-detectable (including 1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1, and 22q11.2 deletions), and genome-wide NIPS-detectable (including variants >7Mb). The theoretical residual risk for clinically significant CNVs was calculated following exclusion of NIPS-detectable findings. RESULTS Of the 7,235 pregnancies, clinically significant CNVs were demonstrated in 87 cases (1.2%). The residual risk following theoretically normal NIPS was 1.07% (1/94) for 3-NIPS, 0.78% (1/129) for 5-NIPS, 0.74% (1/136) for 5-NIPS including common microdeletions, and 0.68% (1/147) for genome wide NIPS. In the subgroup of 4,048 pregnancies with advanced maternal age, the residual risk for clinically significant CNVs following theoretically normal NIPS ranged from 1.36% (1/73) for 3-NIPS to 0.82% (1/122) for genome wide NIPS. In 3,187 pregnancies of women younger than 35 years, this residual risk ranged from 0.69% (1/145) for 3-NIPS to 0.5% (1/199) for genome wide NIPS. CONCLUSIONS The residual risk of clinically significant CNVs in pregnancies without structural sonographic anomalies is appreciable, and depends on NIPS extent and maternal age. This knowledge is important for the patients, the obstetricians and the genetic counselors, in order to facilitate informed decisions regarding prenatal testing and screening options.