Submission Details

Although intragenic deletions in TAOK1 had been observed in large cohort studies of individuals with neurodevelopmental disorders in 2011 and 2018 (PMIDs: 21841781, 29674594), the first report focusing on variants in TAOK1 as a cause of autosomal dominant syndromic intellectual disability was published in 2019 (PMID: 31230721). TAOK1 (thousand and one amino acid kinase 1) encodes the serine/threonine-protein kinase TAO1. Individuals with pathogenic variants in this gene present with variable degrees of developmental delay and/or intellectual disability, behavior problems (including autism in some), hypotonia, macrocephaly, dysmorphic facial features, and joint hypermobility (PMID: 33565190). Truncating variants in this gene have been reported in 18 individuals in 2 publications that included detailed phenotype information and were the basis of this curation (PMIDs: 31230721, 33565190), although only 6 probands were scored in this curation because the maximum score for genetic evidence has been reached. Most variants occurred de novo; in two instances, they were inherited from affected parents. Additional de novo truncating variants have been identified by exome sequencing in affected individuals from large cohort studies of autism spectrum disorder and developmental disorders, but detailed phenotype information is not available in those studies (PMIDs: 31981491, 33057194). Furthermore, nine de novo TAOK1 missense variants were reported in the 2 publications focused on TAOK1 (PMIDs: 31230721, 33565190). Although the clinical interpretation of these variants is difficult in the context of nonspecific phenotypes, functional analysis showed that some missense variants resulted in loss of protein function, while others led to dominant-negative effects (PMID: 33565190). Thus, while the mechanism for disease is predicted to be haploinsufficiency based on protein truncating variants reported in affected individuals and functional studies in patient-derived fibroblasts (PMID: 31230721), further studies are needed to confirm the mechanisms of missense variants. This gene-disease relationship is also supported by experimental evidence, including non-human model organisms (PMIDs: 26996505, 31230721, 33565190) and functional in vitro studies (PMID: 14517247, 33565190). In summary, there is sufficient genetic evidence to support a definitive gene-disease relationship between TAOK1 and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 08/04/21 (SOP Version 8).