RAB3GAP1 – Warburg Micro syndrome

Warburg Micro syndrome is a rare autosomal recessive neuro‐ophthalmologic and endocrinologic disorder characterized by microcephaly, microphthalmia/microcornea, congenital cataracts, optic atrophy, corpus callosum hypoplasia, severe intellectual disability, spasticity, and hypogonadism. Biallelic loss‐of‐function variants in RAB3GAP1 account for approximately 40% of cases, with over 69 different pathogenic alleles reported to date. ([PMID:15696165])

Genetic evidence for the RAB3GAP1–Warburg Micro syndrome association is strong. In the original cohort, homozygous or compound heterozygous inactivating RAB3GAP1 mutations were identified in 12 unrelated families, including nonsense, frameshift, and splice‐site changes, each segregating with disease phenotype and consistent across diverse ethnic backgrounds ([PMID:15696165]). Additional case reports, such as Japanese siblings with a compound heterozygous c.1009C>T (p.Arg337Ter) and c.560G>C (p.Arg187Pro), further support recurrence of loss‐of‐function alleles in affected individuals ([PMID:26421802]).

Inheritance is autosomal recessive, with parents typically heterozygous carriers and multiple affected siblings observed in consanguineous and non-consanguineous pedigrees. Segregation analysis across these families demonstrated complete co-segregation of biallelic RAB3GAP1 variants with the WARBM1 phenotype in 12 affected relatives.

Variant spectrum includes nonsense (e.g., c.1009C>T (p.Arg337Ter)), frameshift (e.g., c.1381del (p.Ala461fs)), and splice-site mutations (e.g., c.748+1G>A) distributed across exons 2–23, without clear genotype–phenotype correlations beyond the nature of the predicted loss of RAB3GAP1 activity.

Functional studies indicate that RAB3GAP1 deficiency disrupts neuronal morphogenesis and exocytic release pathways. Downregulation of RAB3GAP1 in human‐derived neurons reduces neurite outgrowth and branching, implicating impaired Rab3 cycle regulation in neurodevelopmental pathology ([PMID:37385458]). These in vitro findings concord with the human phenotype.

Overall, the evidence supports a Strong ClinGen gene–disease association for RAB3GAP1 and Warburg Micro syndrome, with robust genetic segregation and concordant functional data. Molecular diagnosis of RAB3GAP1 variants enables definitive genetic counseling, early intervention, and tailored supportive therapies.

Key take-home: Biallelic RAB3GAP1 loss-of-function variants cause classic autosomal recessive Warburg Micro syndrome, justifying comprehensive RAB3GAP1 screening in syndromic congenital cataract and microcephaly presentations.

References

• Nature genetics • 2005 • Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. PMID:15696165
• Neurobiology of disease • 2023 • The Warburg micro syndrome protein RAB3GAP1 modulates neuronal morphogenesis and interacts with axon elongation end ER-Golgi trafficking factors. PMID:37385458
• Brain & development • 2016 • Novel RAB3GAP1 compound heterozygous mutations in Japanese siblings with Warburg Micro syndrome. PMID:26421802

Evidence Based Scoring (AI generated)