Prenatal Etiology Diagnosis of Rare Compound Heterozygous PROC Gene Variants in a Fetus With Ocular Ultrasonic Anomaly Using Whole Exome Sequencing.

backgroundThis study aims to present novel compound heterozygous PROC gene variants in a fetus. These variants cause protein C deficiency-associated thrombophilia and are accompanied by prenatal ocular anomalies in the affected fetus.

methodsA fetus presenting with prenatal ocular ultrasound anomalies was enrolled for genetic prenatal diagnosis. Trio whole-exome sequencing (WES) was performed on the fetus and parental samples to explore the genetic etiology. Sanger sequencing was subsequently applied to verify the identified genetic variants.

resultsWES result revealed two likely pathogenic compound heterozygous variants NM_000312.4: c.[378G>A(p.W126*)]; [658C>T(p.R220W)] in PROC gene in the fetus, which were inherited from the parents, respectively. Notably, a likely pathogenic homozygous variant of NM_176824.3:c.728G>A(p.C243Y) in BBS7 gene, and a heterozygous variant of NM_012193.4:c.112G>A(p.G38R) in FZD4 gene, as well as a pathogenic heterozygous variant of NM_000435.3:c.1630C>T(p.R544C) in NOTCH3 gene were observed in the mother, which may explain her clinical abnormalities. The maternal BBS7 variant was transmitted to the fetus, whereas the FZD4 and NOTCH3 variants were not detected in the proband. The father exhibited a clinical phenotype of cleft lip and palate, but no corresponding pathogenic genetic variants were identified.

conclusionThis study first reports two rare compound heterozygous PROC variants in a Chinese fetus, which expands the mutational spectrum of protein C deficiency-related thrombophilia in the Chinese population. Furthermore, our findings highlight the robust clinical application value of trio-WES in the etiological diagnosis of complex prenatal genetic disorders.