Submission Details

AP4E1 loss-of-function variants have been reported in at least 21 individuals from 11 families with autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome (PMID: 32979048). AP4 deficiency results in severe early-onset developmental delay with motor delay and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048, 30543385). Biallelic AP4E1 nonsense, frameshift, splicing and large deletion variants leading to loss of AP4E1 protein function and the AP4 complex have been reported in AP4 deficiency syndrome patients (PMID: 32979048, 21620353, 20972249, 21937992, 23472171). The gene-disease association is further supported by biochemical and functional assays demonstrating loss of AP4 complex function and impaired protein trafficking in fibroblasts from patients with AP4E1 loss-of-function variants (PMID: 31915823). AP4E1 knockout mice demonstrate impaired motor coordination, weak grip strength, thin corpus callosum and impaired protein trafficking, which is consistent with features of AP4 deficiency syndrome (PMID: 29698489). In summary, the AP4E1 gene is definitively associated with autosomal recessive AP4 deficiency syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on December 16, 2020. As of July 2024, this record underwent administrative updates to update scoring to be consistent with SOP Version 10.