1 RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom.
2 Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Exeter, United Kingdom.
3 Department of Biology, Concordia University, Montreal, Quebec, Canada.
4 Department of Biological Sciences, International Islamic University, Islamabad, Pakistan.
5 Institute of Genetics and Molecular and Cellular Biology, Inserm, Illkirch, France.
6 Inserm, University of Bourgogne Franche-Comté, Dijon, France.
7 Department of Molecular Diagnostics, Rehman Medical Institute, Peshawar, Pakistan.
8 Faculty of Health, University of Plymouth, Plymouth, United Kingdom.
9 University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.
10 Wellcome Sanger Instit

The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic sequence alterations in TRAPPC10, 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 TRAPPC10-/- 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 Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm biallelic TRAPPC10 gene 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.