AP1G1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Usmani et al., PMID: 34102099). Of note, AP1G1 has also been implicated in autosomal recessive complex neurodevelopmental disorder (Usmani-Riazuddin syndrome, autosomal recessive). The split curation for Usmani-Riazuddin syndrome, autosomal recessive, is assessed separately.
AP1G1-related autosomal dominant complex neurodevelopmental disorder (also known as Usmani-Riazuddin syndrome, autosomal dominant) is characterized by global developmental delay with variably impaired intellectual development, speech delay, and behavioral abnormalities, including aggression, hyperactivity, and autism spectrum disorder or autistic features. Additional common features include seizures, hypotonia, and distal limb anomalies. Five de novo missense variants and three de novo loss-of-function variants have been reported in nine unrelated patients (PMID: 34102099). This gene-disease relationship is also supported by experimental evidence. AP1G1 interacts with other adaptor protein complex 1 (AP-1) proteins, AP1S1/AP1S2, which have been definitively implicated in neurodevelopmental disorders. AP complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons.
In summary, there is strong evidence to support this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 2, 2022 (SOP Version 9).
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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