AP1S2 was first reported in relation to X-linked syndromic complex neurodevelopmental disorder in 2006 (Tarpey et al., PMID: 17186471). AP1S2 encodes the sigma 2 subunit of the adaptor protein 1 (AP1) complex. AP1 is found in coated vesicles in the Golgi compartment, where it mediates the recruitment of clathrin and the recognition of sorting signals of transmembrane receptors. The clinical features in affected males are highly variable and may include hypotonia, intellectual disability, autism spectrum disorder, seizures, choreoathetosis, microcephaly, and brain malformations such as hydrocephalus, periventricular nodular heterotopia, basal ganglia calcifications, Dandy-Walker malformation, and cerebellar defects.
Seven variants (nonsense and splice) that have been reported in eight probands in five publications (PMIDs: 17186471, 17617514, 18428203, 23756445, 25649377) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function.
This gene-disease relationship is also supported by biochemical function, protein interactions, and a mouse model. Pathogenic variants in other subunits of the AP1 complex are also involved in neurodevelopmental disorders, including AP1S1, AP1B1, and AP1G1.
In summary, there is definitive evidence supporting the relationship between AP1S2 and X-linked syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. It was reevaluated on April 22, 2025 (SOP Version 11). Although new experimental evidence was added, the classification did not change.
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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