Macrocephaly and developmental delay caused by missense variants in RAB5C

Klaas Koop, Weimin Yuan, Federico Tessadori, Wilmer R. Rodriguez-Polanco, Jeremy Grubbs, Bo Zhang, Matt Osmond, Gail Graham, Sarah Sawyer, Erin Conboy, Francesco Vetrini, Kayla Treat, Rafal Płoski, Victor Murcia Pienkowski, Anna Kłosowska, Elizabeth Fieg, Joel Krier, Coralie Mallebranche, Ziegler Alban, Kimberly A. AldingerDeborah Ritter, Ellen MacNamara, Bonnie Sullivan, John Herriges, Joseph T. Alaimo, Catherine Helbig, Colin A. Ellis, Clare Van Eyk, Jozef Gecz, Daniel Farrugia, Ikeoluwa Osei-Owusu, Lesley Adès, Marie Jose Van Den Boogaard, Sabine Fuchs, Jeroen Bakker, Karen Duran, Zachary D. Dawson, Anika Lindsey, Huiyan Huang, Dustin Baldridge, Gary A. Silverman, Barth D. Grant, David Raizen, Gijs Van Haaften, Stephen C. Pak, Holger Rehmann, Tim Schedl, Peter Van Hasselt

Research output: Contribution to journalArticlepeer-review


Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.

Original languageEnglish
Pages (from-to)3063-3077
Number of pages15
JournalHuman molecular genetics
Issue number21
StatePublished - Nov 1 2023


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