This variant is classified as a variant of unknown significance because its contribution to a syndromic intellectual developmental disorder has not been confirmed.
In 5 members of a large multigenerational consanguineous family from Saudi Arabia with a syndromic intellectual developmental disorder, Mohamoud et al. (2018) identified a homozygous c.319T-A transversion (c.319T-A, NM_04108) in exon 4 of the TRAPPC6A gene, resulting in a tyr107-to-asn (Y107N) substitution at a highly conserved residue. The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The same homozygous variant was subsequently found in 1 unrelated Turkish individual in the Greater Middle East Variome (GME) database, which is enriched for individuals with neurodevelopmental disabilities. The variant was not found in 40 control Saudi chromosomes or an in-house database of 40 exomes; it was also filtered against the ExAC, 1000 Genomes Project, dbSNP, and Exome Variant Server databases and was not present in homozygous state in these databases. Transfection of the mutation into HEK293 cells showed that the mutant protein was more stable than the wildtype protein, which was subject to proteasomal degradation. The authors speculated that abnormal build-up of the mutant protein may adversely affect protein trafficking. Studies of patient cells were not performed. The patients had normal motor development with impaired intellectual development and learning difficulties, speech delay, and dysmorphic facies, including broad forehead, large ears, anteverted nares, and thick upper lip. Other more variable features included clinodactyly of the fifth toe and postaxial polydactyly of the hands and/or feet. The IQ of 3 patients, ranging in age from 7 to 12 years, was 67, 68, and 73. Exome sequencing revealed that all affected individuals in the Saudi family also carried homozygous variants in 4 other genes (RSPH6A, 607548; ANKK1, 608774; AMOTL1, 614657; and ALKBH8, 613306) that also segregated with the disorder in the family; a contributing effect of these variants could not be excluded.
