RT Journal Article SR Electronic T1 Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 753 OP 764 DO 10.1136/jmedgenet-2018-105441 VO 55 IS 11 A1 Miroslav P Milev A1 Claudio Graziano A1 Daniela Karall A1 Willemijn F E Kuper A1 Noraldin Al-Deri A1 Duccio Maria Cordelli A1 Tobias B Haack A1 Katharina Danhauser A1 Arcangela Iuso A1 Flavia Palombo A1 Tommaso Pippucci A1 Holger Prokisch A1 Djenann Saint-Dic A1 Marco Seri A1 Daniela Stanga A1 Giovanna Cenacchi A1 Koen L I van Gassen A1 Johannes Zschocke A1 Christine Fauth A1 Johannes A Mayr A1 Michael Sacher A1 Peter M van Hasselt YR 2018 UL http://jmg.bmj.com/content/55/11/753.abstract AB Background The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging.Objective The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia.Methods Whole exome sequencing was used to identify pathogenic variants in the two individuals. Biochemical and cell biological analyses were performed on fibroblasts from these individuals and a yeast two-hybrid analysis was used to assess protein-protein interactions.Results Probands shared a homozygous TRAPPC2L variant (c.109G>T) resulting in a p.Asp37Tyr missense variant. TRAPPC2L is a component of transport protein particle (TRAPP), a group of multisubunit complexes that function in membrane traffic and autophagy. Studies in patient fibroblasts as well as in a yeast system showed that the p.Asp37Tyr protein was present but not functional and resulted in specific membrane trafficking delays. The human missense mutation and the analogous mutation in the yeast homologue Tca17 ablated the interaction between TRAPPC2L and TRAPPC10/Trs130, a component of the TRAPP II complex. Since TRAPP II activates the GTPase RAB11, we examined the activation state of this protein and found increased levels of the active RAB, correlating with changes in its cellular morphology.Conclusions Our study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.