Hydrocephaly associated with compound heterozygous alterations in TRAPPC12
Jennifer M Gass1, Barbara B Head2, Sally M Shields2
1J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
Insights
Genetic variants in the TRAPPC12 gene were linked to recurrent fetal hydrocephalus in a family. This discovery offers new insights into the genetic causes of this complex brain development disorder.
Area of Science:
- Genetics
- Developmental Biology
- Neurology
Background:
- Hydrocephalus, a condition of increased cerebrospinal fluid, affects 1 in 1,000 live births.
- It is a heterogeneous disorder with numerous genetic and environmental causes, complicating diagnosis.
Observation:
- Whole exome sequencing was performed on two fetuses with hydrocephalus and their parents from a family with three affected pregnancies.
- The study identified compound heterozygous alterations in the TRAPPC12 gene in the affected fetuses.
Findings:
- The identified TRAPPC12 variants, one causing premature transcript termination and the other affecting RNA splicing, were inherited from the parents.
- These compound heterozygous variants in TRAPPC12 may impair Golgi trafficking and mitosis.
Implications:
- Disruption of TRAPPC12 function could lead to abnormal brain embryogenesis, resulting in fetal hydrocephalus and recurrent pregnancy loss.
- This finding expands the known genetic factors contributing to hydrocephalus and recurrent pregnancy loss.
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.
