An Autosomal Recessive form of Cornelia de Lange Syndrome Due to Mutations in TRMT61A Gene: A Case Report

Background: Cornelia de Lange syndrome is a rare genetic disorder presenting with craniofacial dysmorphia, developmental delay, intellectual disabilities, upper limb abnormalities and gastrointestinal problems. The disease is genetically heterogenous and the underlying genetic cause in unknown in around 30% of the cases.

Case Presentation: A Palestinian family visited our department for genetic counseling. The non-consanguineous parents have only two (4 and 2 years old) daughters, both presented with features consistent with Cornelia de Lange syndrome. Whole exome sequencing revealed two previously unknown coding variants in the autosomal TRMT61A, a gene that has not been linked to any human disease before. TRMT61A codes for the catalytic subunit of tRNA (adenine-N1-)-methyltransferase. The mother harbored an in-frame deletion variant c.478_483delCGCACC (p.R160_T161del), whereas the father carried a missense variant c.323G>T (p.C108F). Both variants are novel and were predicted as "damaging". So far, no autosomal recessive forms of the disease has been described in the literature. The carrier states of the parents and the existence of the two variants in compound heterozygous forms in both girls was further confirmed by allele-specific PCR. In their next pregnancy, prenatal diagnosis indicated that the fetus is a carrier of the mother's variant and the pregnancy culminated in the birth of a healthy baby girl.

Conclusion: It can be concluded that the TRMT61A mutations are the cause of the disease features observed in this family and supports the proposal that RNA modification defects are involved in the molecular pathogenesis of Cornelia de Lange syndrome.