Submission Details

Variants in the ATP6AP2 gene were first reported in relation to X-linked ATP6AP2-related disorder in 2005 (Ramser, et al., PMID: 15746149). The affected male individuals are characterized by global developmental delay, intellectual impairment, spasticity, seizures, infantile onset of liver failure, recurrent infections, and features of parkinsonism (rigidity, resting tremor, and bradykinesia). These phenotypes may not appear in all individuals. The age of onset and expressivity are also variable. Evidence supporting this gene-disease relationship includes case-level data and segregation data. ATP6AP2 variants have been reported in at least seven probands in six publications (PMID: 15746149, 23595882, 26467484, 29127204, 30125339, and 30985297). Noteworthy, three of the reported splicing variants lead to exon 4 skipping in the ATP6AP2 gene via mRNA studies (PMID: 15746149, 23595882, 26467484, and 30985297), although the affected individuals manifest variable phenotypes. The gene-disease association is also supported by animal models and in vitro rescue experiments (PMID: 26376863 and 30985297). Defects in the ATP6AP2 gene may result in 1) MRXSH (mental retardation, X-linked, syndromic, Hedera type), 2) Congenital disorder of glycosylation, type IIr, and 3) Parkinsonism with spasticity, X-linked (see OMIM). In summary, ATP6AP2 is definitively associated with X-linked ATP6AP2-related disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on 9/14/20 (SOP Version 7).