De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.

07. Februar, 2019

Platzer K1, Sticht H2, Edwards SL3, Allen W4, Angione KM5, Bonati MT6, Brasington C7, Cho MT8, Demmner LA7, Falik – Zaccai T9, Gamble CN10, Hellenbroich Y11, Iascone M12, Kok F13, Mahida S14, Mandel H15, Marquardt T16, McWalter K8, Panis B17, Pepler A18, Pinz H19, Ramos L13, Schinde DN20, Smith-Hicks C14, Stegmann APA21, Stöbe P18, Stumpel CTRM21, Wilson C4, Lemke JR22, Di Donato N23, Miller KG3, Jamra R22.


Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.