RAB3GAP2 – Warburg Micro Syndrome 2

Warburg Micro syndrome 2 (MONDO:0013641) is a rare autosomal recessive neuro-ophthalmologic disorder defined by congenital cataracts, microphthalmia, microcephaly, and profound developmental delay. Pathogenic biallelic variants in RAB3GAP2 (HGNC:17168), which encodes the noncatalytic subunit of the RAB3GAP complex regulating RAB3/RAB18 cycling, underlie the disease mechanism.

Whole-exome sequencing in a consanguineous Turkish pedigree identified a homozygous splice-site mutation, c.1998+1G>A, segregating in four affected siblings with developmental cataract, global developmental delay, and speech delay ([PMID:29419336]). Independently, a second consanguineous family harbored a homozygous in-frame deletion, c.499_507del (p.Phe167_Thr169del), in a single proband with congenital cataracts, microphthalmia, polymicrogyria, corpus callosum hypoplasia, and severe developmental delay ([PMID:20967465]). These observations account for five probands across two unrelated families, with segregation data supporting autosomal recessive inheritance.

Reported pathogenic variants in RAB3GAP2 include one canonical splice-site and one small in-frame deletion, both predicted to disrupt protein function. No recurrent or founder variants have been described, and allele frequency data remain limited.

Functional analyses demonstrate that severe loss-of-function RAB3GAP2 mutations abolish RAB3GAP complex activity, perturbing RAB3/RAB18 GTPase cycling and recapitulating the Warburg Micro phenotype. Hypomorphic RAB3GAP2 alleles yield the milder Martsolf syndrome, illustrating a phenotypic severity gradient governed by mutation type ([PMID:20967465]).

No studies refute the association between RAB3GAP2 and Warburg Micro syndrome 2. The clinical and experimental concordance across independent families substantiates the gene–disease link.

Key take-home: Biallelic loss-of-function variants in RAB3GAP2 cause Warburg Micro syndrome 2 and should be included in diagnostic gene panels for congenital cataracts with severe developmental delay.

References

• Ophthalmic genetics • 2018 • Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome? PMID:29419336
• Human genetics • 2011 • A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. PMID:20967465

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