AP4M1 loss-of-function variants were first reported in relation to autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome in 2009 (PMID: 19559397). AP4 deficiency results in severe early-onset developmental delay with motor and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048). At least 59 individuals from 34 families with biallelic AP4M1 nonsense, frameshift, splicing and large deletion variants leading to loss of protein function have been reported (PMIDs: 19559397, 24700674, 25496299, 29096665, 32979048). This gene-disease relationship is also supported by biochemical and functional evidence demonstrating loss of AP4 complex function and abnormal glutamate receptor GluRĪ“2 staining in dendrites of post-mortem brain samples from patients with AP4M1 loss-of-function variants (PMID: 19559397).
In summary, there is definitive evidence supporting the relationship between AP4M1 and autosomal recessive AP4 deficiency syndrome. 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 April 7, 2021 (SOP Version 8).
AP4M1 loss-of-function variants were first reported in relation to autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome in 2009 (PMID: 19559397). AP4 deficiency results in severe early-onset developmental delay with motor and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048). At least 59 individuals from 34 families with biallelic AP4M1 nonsense, frameshift, splicing and large deletion variants leading to loss of protein function have been reported (PMIDs: 19559397, 24700674, 25496299, 29096665, 32979048). The gene-disease association is further supported by biochemical and functional evidence demonstrating loss of AP4 complex function and abnormal glutamate receptor GluRĪ“2 staining in dendrites of post-mortem brain samples from patients with AP4M1 loss-of-function variants (PMID: 19559397). In summary, the AP4M1 gene is definitively associated with autosomal recessive AP4 deficiency syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 04/07/2021 (SOP Version 8).
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