Background: Hydrocephalus is characterized by increased cerebrospinal fluid within the brain, a causally heterogeneous disorder estimated to affect 1 per 1,000 live births, with the most severe cases often leading to fetal demise. The large number of known genetic and environmental factors that contribute to hydrocephalus makes the differential diagnosis challenging.
Cases: Three consecutive pregnancies of an unrelated couple were found by ultrasound to carry fetuses with hydrocephaly. DNA from two affected fetuses and the parents were subjected to whole exome sequencing. Heterozygous alterations in the TRAPPC12 gene were identified in the parents and compound heterozygous alterations were present in the two affected fetuses. The variant from the father (c.954del) leads to a premature termination of the transcript; the variant from the mother (c.1677+5G>A) affects a splice site which leads to aberrant splicing of the TRAPPC12 transcript.
Conclusion: Compound heterozygous variants in TRAPPC12, which encodes a protein involved in Golgi trafficking and mitosis, may disrupt normal brain embryogenesis leading to hydrocephalus and recurrent pregnancy loss.
Keywords: TRAPPC12; autosomal recessive; hydrocephaly; malformation; prenatal diagnosis.
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