Long‐Term Follow Up of Two Patients With Variants in the Cluster 1031‐1159 of TRRAP Gene: Expanding the Phenotype of Developmental Delay With or Without Dysmorphic Facies and Autism

The transformation/transcription domain-associated protein (TRRAP) gene encodes a large multidomain protein, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. TRRAP is a component of the histone acetyltransferase (HAT) complex, and it plays an important role in gene transcription, DNA repair, and cell-cycle regulation. Heterozygous missense variants in the TRRAP gene have been associated with a multiple system condition known as developmental delay with or without dysmorphic facies and autism (DEDDFA; OMIM #618454), hearing loss, and different types of cancer. Strong genotype-phenotype correlation has been observed in DEDDFA, where missense variants located in the clustering between residues 1031-1159 result in more pronounced facial anomalies associated with a variable degree of intellectual disability. Here, we report two Brazilian females with syndromic orofacial cleft, presenting very similar atypical facial phenotypes and multisystem anomalies. Both had a severe phenotype with global developmental delay, ranging from moderate to severe, and one of them had a severe behavior disorder associated with non-verbal autism while the other had inguinal cancer. Next-generation sequencing showed that both displayed heterozygous missense variants in the TRRAP gene, clustering at the 1031-1159 amino acid residues. These cases reinforce the genotype-phenotype correlation of variants in the TRRAP gene with a possible new domain in the cluster 1031-1159.