Abidi Syndrome and Another Family With X-Linked Intellectual Disability Have TAF1 Variants and Reduced...

Genetic alterations in TATA box binding protein-associated factor 1 (TAF1) have been found in an X-linked intellectual disability (XLID) syndrome with variable somatic features (OMIM 300966) and X-linked dystonia-Parkinsonism syndrome (OMIM 314250). Abidi syndrome (OMIM 300262) was first described in a large, three-generation family containing eight affected males with intellectual disability and variable somatic features. A single base substitution that alters the translation initiation codon of TAF1, c.1A>C (p.Met1?), was found in affected males from the original Abidi syndrome family by X-exome sequencing. A missense variant in the C-terminal domain of TAF1, c.4286A>C (p.Gln1429Pro), was identified in another XLID family including three males with intellectual disability and variable somatic features using the same approach. Both variants were found segregating with the phenotype in the respective families and are predicted to be deleterious by in silico analysis. The N- and C-terminal domains of TAF1 are known to possess a serine/threonine kinase activity that selectively phosphorylates RNA polymerase II-associated protein 74 (RAP74). Lymphoblasts carrying either the p.Met1? or the p.Gln1429Pro variants from probands in these two families were studied using a phosphorylation-specific antibody and found to have reduced phosphorylation of RAP74. This study expands the phenotypic spectrum of TAF1-related XLID and implicates reduced RAP74 phosphorylation as a potential mechanism.