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

Platzer K, Sticht H, Edwards SL, Allen W, Angione KM, Bonati MT, Brasington C, Cho MT, Demmer LA, Falik-Zaccai T, Gamble CN, Hellenbroich Y, Iascone M, Kok F, Mahida S, Mandel H, Marquardt T, Mcwalter K, Panis B, Pepler A, Pinz H, Ramos L, Shinde DN, Smith-Hicks C, Stegmann APA, Stoebe P, Stumpel CTRM, Wilson C, Lemke JR, Di Donato N, Miller KG, Jamra R (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 104

Pages Range: 203-212

Journal Issue: 2

DOI: 10.1016/j.ajhg.2018.12.008

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Leipzig Germany (DE) Zuyderland Medical Center Netherlands (NL) Saint Louis University (SLU) United States (USA) (US) Ambry Genetics United States (USA) (US) Universitätsklinikum Münster Germany (DE) CeGaT GmbH Germany (DE) GeneDX United States (USA) (US) Johns Hopkins University (JHU) United States (USA) (US) Maastricht University Netherlands (NL) North Carolina Biotechnology Center United States (USA) (US) Oklahoma Medical Research Foundation (OMRF) United States (USA) (US) Levine Children’s Hospital United States (USA) (US) University of Colorado System United States (USA) (US) Galilee Medical Center / המרכז הרפואי לגליל Israel (IL) Universität zu Lübeck Germany (DE) Istituto Scientifico Ospedale San Luca (Istituto Auxologico Italiano) Italy (IT) Technische Universität Dresden Germany (DE) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Azienda Ospedaliera Papa Giovanni XXIII Italy (IT)

How to cite

APA:

Platzer, K., Sticht, H., Edwards, S.L., Allen, W., Angione, K.M., Bonati, M.T.,... Jamra, R. (2019). De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. American Journal of Human Genetics, 104(2), 203-212. https://dx.doi.org/10.1016/j.ajhg.2018.12.008

MLA:

Platzer, Konrad, et al. "De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies." American Journal of Human Genetics 104.2 (2019): 203-212.

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