The MAPK8IP3 gene is located on chromosome 16 at 16q13.3 and encodes the Mitogen-Activated Protein Kinase 8 Interacting Protein 3, one of the family of JNK-interacting protein group of scaffold proteins. MAPK8IP3 was first reported in relation to autosomal dominant MAPK8IP3-related neurodevelopmental disorders in 2019 (Platzer et al., PMID: 30612693). 7 variants (including 4 missense, 2 nonsense, and 1 frameshift) have been reported in 9 probands in 2 publications (PMID: 30612693; Iwasawa et al., 2019, PMID: 30945334) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of the disease is not yet established. However, it is known that the protein encoded by MAPK8IP3 acts as a regulator of vesicle transport and promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Both missense variants located in functional domains and null variants, all of which are de novo, are implicated in disease. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, rescue and expression studies) (Gowrishankar et al., 2017, PMID: 28784610; PMID: 30612693). In summary, MAPK8IP3 is definitively associated with autosomal dominant MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 10.26.2021 (SOP Version 8).
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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