ANKRD17 belongs to family of proteins characterized by the presence of ankyrin repeats, one of the commonest structural motif in eukaryocytes. The ankyrin repeat is a highly conserved motif thought to play a role in protein-protein interactions. The Drosophila ortholog of ANKRD17, functions in Hippo, a key growth regulating pathway, as a co-factor of Yorkie.
ANKRD17 is highly intolerant of loss of function in the general population, with a PLI score of 1.0 on Gnomad. The mutational spectrum of affected individuals to date is suggestive of haploinsufficiency as the underlying mechanism of disease, with a predominance of truncating or essential spice variants. Disease-causing missense variants in highly conserved amino acids, particularly within the ankyrin repeat domain have also been reported. While most variants arise de novo, inheritance from a mildly affected parent is possible. To date, individuals have been diagnosed following clinical or research whole exome or genome sequencing.
While the exact mechanism by which ANKRD17 disruption leads to the neurodevelopmental phenotype is not known, it is possible that dysregulation of the Hippo pathway is the basis for this disorder.