Macrocephaly and developmental delay caused by missense variants in RAB5C.

Area of Science:

• Genetics
• Molecular Biology
• Neurodevelopmental Disorders

Background:

• Rab GTPases regulate intracellular vesicular trafficking.
• RAB5C is crucial for endocytosis, protein recycling, and signaling.
• Genetic variants in RAB5C can impact cellular functions.

Purpose of the Study:

• To investigate the role of RAB5C variants in human neurodevelopmental disorders.
• To characterize the functional consequences of identified RAB5C variants.
• To establish the association between RAB5C variants and specific clinical phenotypes.

Main Methods:

• Clinical analysis of 12 individuals with de novo RAB5C variants.
• In vitro biochemical assays to assess variant effects on protein function.
• In vivo studies in C. elegans and zebrafish to evaluate developmental impacts.
• Bioinformatic analysis of variant pathogenicity.

Main Results:

• Nine different heterozygous de novo RAB5C variants were identified in 12 individuals.
• Missense variants were associated with macrocephaly and mild-to-moderate developmental delay.
• Loss-of-function variants correlated with refractory epilepsy, intellectual disability, and normal head circumference.
• In vitro and in vivo studies confirmed the damaging effects of four missense variants, impacting endocytic pathway function and protein interactions, with some acting via a dominant-negative mechanism.

Conclusions:

• RAB5C missense variants are associated with a neurodevelopmental disorder characterized by macrocephaly and developmental delay.
• Disruption of the endocytic pathway by RAB5C variants underlies the observed phenotypes.
• The study highlights RAB5C as a significant gene in neurodevelopment and provides insights into variant-specific disease mechanisms.