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

Konrad Platzer, Heinrich Sticht, Stacey L Edwards, William Allen, Kaitlin M Angione, Maria T Bonati, Campbell Brasington, Megan T Cho, Laurie A Demmer, Tzipora Falik-Zaccai, Candace N Gamble, Yorck Hellenbroich, Maria Iascone, Fernando Kok, Sonal Mahida, Hanna Mandel, Thorsten Marquardt, Kirsty McWalter, Bianca Panis, Alexander PeplerHailey Pinz, Luiza Ramos, Deepali N Shinde, Constance Smith-Hicks, Alexander P A Stegmann, Petra Stöbe, Constance T R M Stumpel, Carolyn Wilson, Johannes R Lemke, Nataliya Di Donato, Kenneth G Miller, Rami Jamra

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Abstract

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
DOIs
Publication statusE-pub ahead of print - Dec 31 2018

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Platzer, K., Sticht, H., Edwards, S. L., Allen, W., Angione, K. M., Bonati, M. T., Brasington, C., Cho, M. T., Demmer, L. A., Falik-Zaccai, T., Gamble, C. N., Hellenbroich, Y., Iascone, M., Kok, F., Mahida, S., Mandel, H., Marquardt, T., McWalter, K., Panis, B., ... Jamra, R. (2018). De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2018.12.008