Submission Details

ANKRD17 is an ankyrin repeat domain-containing protein implicated in cell cycle progression, immune regulation , and cell growth, differentiation, proliferation, and migration through the Yorkie/Hippo/YAP pathway. ANKRD17 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder, also known as Chopra-Amiel-Gordon Syndrome (CAGS) (OMIM:619504), in 2021 (Chopra et al., PMID: 33909992). Pathogenic variants in ANKRD17 cause a syndromic neurodevelopmental disorder characterized by intellectual disability/developmental delay particularly affecting speech and facial dysmorphism. Additional features may include growth deficiency, feeding difficulties, ophthalmological abnormalities, gait/balances disturbances, recurrent infections, autism and epilepsy. The disease entity has been curated under syndromic complex neurodevelopmental disorder. The proposed mechanism is heterozygous loss of function, supported by the mutational spectrum and the intolerance to variation in the general population. Evidence supporting this gene-disease relationship includes case-level data.

Ten variants (3 nonsense variants, 2 frameshift variants, 3 missense variants, and 1 essential splice site variant) that have been reported in 11 probands in one publication (PMID: 33909992) are included in this curation. Of these 11 probands, one had a variant that was inherited from an affected parent (not counted as a proband) and the remaining 10 probands had de novo variants, including one proband with a variant shared with her monozygous twin (not counted as a proband). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Individuals with atypical phenotypes harboring missense ANKRD17 variants, , including one case reported by Silverstein et al. (PMID: 36277850) with an intracranial hemorrhage, and one case in the Brain Gene Registry with severe hypertension have been noted. The significance of these reports is unclear. The homozygous mouse model is embryonic lethal due to failure of vascular development (Hou et al., 2009, PMID: 19619540), so brain and behavior is not able to be studied in this model system.

In summary, there is definitive evidence to support the relationship between ANKRD17 and autosomal dominant syndromic complex neurodevelopmental disorder. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism GCEP on March 9, 2023. It was reevaluated on December 12, 2024. As a result of this reevaluation, the classification increased from Strong to Definitive because three years have elapsed. No new evidence has been reviewed or added.