ADCY5 was first reported in relation to dyskinesia with orofacial involvement in 2012 (Chen et al., PMID: 22782511). Dyskinesia with orofacial involvement is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of a combination of chorea, athetosis, dystonia, and myoclonus. Variants in ADCY5 have been reported in individuals with the following disease entities: autosomal dominant dyskinesia with orofacial involvement (OMIM: 606703), autosomal recessive dyskinesia with orofacial involvement (OMIM: 619647), and autosomal recessive neurodevelopmental disorder with hyperkinetic movements and dyskinesia (OMIM: 619651). The phenotype of affected individuals varies greatly, with overlap between the dominant and recessive cases. Although the recessive cases tend to be more severe than the dominant cases, it is postulated that the severity of phenotypes is related to where the variant is located in the gene rather than the inheritance pattern (PMID: 26537056, 31538084). Variants in the C1b domain generally cause mild phenotypes, while those in the C1a and C2a domain lead to more moderate to severe phenotypes (PMID: 26537056, 31538084). Per criteria outlined by the ClinGen Lumping and Splitting guidance, all three disease entities have been lumped into one disease entity of semi-dominant dyskinesia with orofacial involvement.
Seventeen variants (missense, splice-site, deletion, frameshift) that have been reported in 17 probands from 10 publications (PMIDs: 22782511, 24700542, 25545163, 27052971, 28971144, 27666935, 30975617, 35002175, 33704598, 34631954) are included in this curation. Variants in this gene segregated with disease in at least 22 family members (PMID: 22782511, 26537056, 30975617). More information is available in the literature, but the maximum score for genetic evidence has been reached (12 points). This gene-disease relationship is also supported by functional alteration studies (PMIDs: 30772269). Two knockout mouse models showed contradictory results, so these models were not scored since we are unclear of the relevance of the models (PMIDs: 12223546, 12665504).
In summary, there is definitive evidence to support the relationship between ADCY5 and semi-dominant dyskinesia with orofacial involvement. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on September 5th, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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