Influence of validating the parental origin on the clinical interpretation of fetal copy number variations in 141 core family cases

Abstract

BACKGROUND: The sources and variants types of the copy number variations (CNVs) in prenatal fetal, and the critical role of parental origin on the interpretation of fetal CNVs are unclear. METHODS: One hundred and forty-one prenatal core families with abnormal CNVs were selected and performed by low-coverage massively parallel CNV sequencing (CNV-seq). RESULTS: The data showed that 72.3% of fetal CNVs were derived from parents, and 27.7% were new variations. Sixty-three cases were heterozygous deletion, 70 cases were threefold duplication, six cases were complex deletion and duplication, and two cases were fourfold repeats. That means the rate of heterozygous deletion and duplication was approximate one. In addition, in parental-derived fetal abnormal CNVs reports, before validating parental origin, 62 CNVs were variants of uncertain significance (VUS), 15 CNVs were likely benign, 20 CNVs were likely pathogenic, and 5 CNVs were pathogenic. However, after validating parental origin, the total clinical significance changed into 12 VUS, 89 likely benign, 1 likely pathogenic, and 0 pathogenic. The clinical interpretation of 78.4% fetal CNVs was changed and tended to be benign after parental CNVs were detected. Besides, we followed up all families. 93.3% parental-derived fetal and 30.3% fetus in new mutation group were born healthy. CONCLUSION: Parental origin verification has an important significance for interpretation on the clinical significance of fetal CNVs.