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.
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany. Electronic address: email@example.com.
- Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany
- Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
- Department of Genetics, Fullerton Genetics Center, Asheville, NC 28803, USA.
- Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO 80045, USA.
- Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy.
- Department of Pediatrics, Clinical Genetics, Levine Children’s Hospital at Carolina Healthcare System, Charlotte, NC 28203, USA.
- GeneDx, Gaithersburg, MD 20877, USA.
- Institute of Human Genetics, Galilee Medical Center, Nahariya 22100, Israel; The Azrieli School of Medicine, Bar-Ilan University, Safed 1311502, Israel.
- Department of Pediatrics, University of Texas Health Medical School, Houston, TX 77030, USA.
- Institute of Human Genetics, University of Lübeck, Lübeck 23562, Germany.
- Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo 24127, Italy.
- Mendelics Genomic Analysis, São Paulo 04013-000, Brazil.
- Department of Neurology, Kennedy Krieger Institute, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Institute of Human Genetics, Galilee Medical Center, Nahariya 22100, Israel.
- Department of Pediatrics, University Hospital Münster, Münster 48149, Germany.
- Department of Pediatrics, Zuyderland Medical Center, Heerlen and Sittard 6419, the Netherlands.
- CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen 72076, Germany.
- Division of Medical Genetics, Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
- Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
- Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht 6229, the Netherlands.
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany.
- Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden 01307, Germany.