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Here we identified biallelic variants in <jats:italic>TRAPPC10<\/jats:italic>, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9\/10 reduction phenotype was recapitulated in <jats:italic>TRAPPC10<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of <jats:italic>Trappc10<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a <jats:italic>Trappc9<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mouse model. Together these studies confirm autosomal recessive <jats:italic>TRAPPC10<\/jats:italic> variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010114","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T18:51:43Z","timestamp":1647543103000},"page":"e1010114","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6764-253X","authenticated-orcid":true,"given":"Lettie 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