Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice

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. Author summaryMicrocephalic neurodevelopmental disorders are a group of conditions that are often inherited in families, involving small head size and abnormal brain development and function. This often results in delayed development of an affected child, affecting their movement, language and/or non-verbal communication and learning, as well as seizures and neuropsychiatric problems. A group of proteins called the transport protein particles (TRAPPs) are important for the transport of cargos inside cells. Alterations within a number of the TRAPP proteins have previously been associated with human inherited diseases called the 'TRAPPopathies', which involve neurodevelopmental and skeletal abnormalities. Here we show that TRAPPC10 gene alterations cause a new TRAPPopathy microcephalic neurodevelopmental disorder, and we provide a detailed clinical description of the condition termed 'TRAPPC10-related disorder'. Our studies in mice lacking the TRAPPC10 gene identified similar features to those of affected humans, including small brain size and skeletal abnormalities. Our molecular studies showed that an affected individual with an alteration in the TRAPPC10 gene has no functional TRAPPC10 protein in their cells, which in turn causes a reduction in levels of another important TRAPP molecule, TRAPPC9. Cells lacking TRAPPC10 also display abnormalities in cellular transport processes. Together our data confirm alterations in TRAPPC10 as a cause of a microcephalic neurodevelopmental disorder in both humans and mice.