Genetic Testing of Fetal Loss of Heterozygosity Using Single Nucleotide Polymorphism Array and Whole Exome Sequencing

Abstract Background To explore the clinical significance of fetal loss of heterozygosity (LOH), identified by single-nucleotide polymorphism array (SNP array). Methods We retrospectively reviewed data form pregnant women who underwent invasivediagnostic procedure at prenatal diagnosis centers in Southeastern China from December 2016 to December 2021. SNP array was performed by the Affymetrix CytoScan 750K array platform. Fetuses with LOH (10 Mb as the threshold or over 5 Mb involving imprinted chromosomes) were further identified by parental verification, MS-MLPA, and/or trio whole exome sequencing (trio-WES), and the genetic results, fetal clinical manifestations, and perinatal outcome were comprehensively analyzed. Results Of 11 062 fetuses, 106 (0.96%) with LOH exhibiting a neutral copy number were detected; in 88 (83.0%) of these, LOH occurred in a single chromosome, while 18 (17.0%) fetuses had multiple LOHs on different chromosomes. A total of 66 fetuses had ultrasound anomalies (UAs); the most frequent UA was fetal growth restriction (18/66 (27.3%)). Further genetic analysis was performed in 42 cases (21 cases by parental SNP array verification and 21 cases by trio-WES), in which, we found clinically relevant uniparental disomy in 12 cases, pathogenic variants in five cases, likely pathogenic variants in four cases, variant of unknown significance in six cases, and identity by descent in eight cases. Significantly, the rate of adverse pregnancy outcomes in fetuses with LOH and UAs (24/66 (36.4%)) was higher than in those without UAs (6/40 (15.0%)) ( p < 0.05). Conclusions Fetuses with LOH is not uncommon. Various molecular genetic testing techniques, such as parental SNP array verification, trio-WES, MS-MLPA, regular and systematic ultrasonic monitoring, and the placental study when necessary, should be performed to accurately assess the prognosis of fetal LOH and guide the affected pregnancy management.