Abstract / Summary
Abstract Background Holoprosencephaly (HPE) is the most common congenital malformation of the forebrain, caused by impaired cleavage of the prosencephalon. Prenatal ultrasound enables early screening, however, recurrence can be due to genetic causes. This study aimed to investigate the genetic basis of recurrent fetal HPE in a family and provide evidence for precise prenatal diagnosis and genetic counseling. Methods A 34-year-old woman with two consecutive pregnancies complicated by fetal alobar HPE (diagnosed by prenatal ultrasound at 13 weeks of gestation) was enrolled. Chromosome karyotype analysis, whole exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA) were performed on the fetuses and their family members. Prenatal ultrasound and MLPA were used for monitoring in the third pregnancy. Results Karyotype analysis showed no abnormalities in either the fetuses or the parents. WES revealed a 21.49 kb heterozygous deletion at 13q32.3 in both the mother and the two affected fetuses, which completely covered the ZIC2 gene (HPE5 subtype). The mother had mild facial phenotypes (broad forehead, sloping forehead, upslanting palpebral fissures, mild epicanthic folds, and arched eyebrows) but normal intelligence. MLPA confirmed the deletion and excluded it in other family members (father, maternal grandparents, and brother). In the third pregnancy, MLPA showed no ZIC2 gene deletion, and prenatal ultrasound at 15 and 21 weeks revealed no structural abnormalities. A healthy infant was delivered successfully. Conclusions The recurrent fetal alobar HPE in this family was caused by a maternally inherited 13q32.3 deletion encompassing the ZIC2 gene. The combined use of prenatal ultrasound (especially first-trimester screening) and genetic technologies (WES and MLPA) is crucial for etiological diagnosis, genetic counseling, and guiding subsequent pregnancies in families with recurrent HPE.