RAB3GAP2 – Warburg Micro Syndrome

RAB3GAP2 has been robustly associated with Warburg Micro Syndrome, a severe neurodevelopmental disorder characterized by congenital cataracts, hypogonadism, and intellectual disability. Multiple independent case reports and series have documented biallelic mutations in RAB3GAP2 that co‐segregate with features overlapping Warburg Micro Syndrome, thus providing strong genetic evidence for its pathogenicity (PMID:16532399).

In one key study, a homozygous missense variant, c.3154G>T (p.Gly1052Cys), was identified in a kindred with congenital cataracts, hypogonadism, and mild mental retardation. This report provided both clinical and molecular confirmation that disruptions in RAB3GAP2 contribute to the disease phenotype, with the variant segregating in an autosomal recessive pattern (PMID:16532399).

Additional case reports have expanded the genetic spectrum; for instance, a splice site mutation, c.1998+1G>A, was reported in a Turkish family with four affected siblings, further supporting autosomal recessive inheritance and showing additional segregation of the mutant allele in affected relatives (PMID:29419336).

Moreover, a recurrent in‐frame deletion, c.499_507del (p.Phe167_Thr169del), has been documented in separate families. This variant has been associated with a more severe presentation of Warburg Micro Syndrome, demonstrating the phenotypic variability that correlates with the nature and severity of the mutation (PMID:20967465).

Functional studies lend further support to this association. Expression analyses in zebrafish embryos and patient‐derived fibroblast assays have revealed abnormal mRNA splicing and impaired protein function, consistent with a loss‐of‐function mechanism. These experimental findings are concordant with the clinical phenotypes observed in patients and bolster the pathogenic role of RAB3GAP2 in neurodevelopment (PMID:20967465).

In summary, the integration of genetic data—encompassing missense, splice site, and small in‑frame deletion variants—with robust functional evidence provides a strong rationale for the pathogenic role of RAB3GAP2 in Warburg Micro Syndrome. This comprehensive evidence supports the clinical utility of genetic testing for RAB3GAP2 variants for diagnostic decision‑making, with implications for commercial test development and future publication.

References

• American journal of human genetics • 2006 • Mutation in Rab3 GTPase-activating protein noncatalytic subunit in a kindred with Martsolf syndrome PMID:16532399
• 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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