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RAB3GAP2 (HGNC:17168) is implicated in Martsolf syndrome (MONDO:0023910), a rare autosomal recessive disorder characterized by congenital cataracts, global developmental delay, and delayed speech. Several independent case reports and multi‐patient studies have described affected individuals harboring biallelic mutations in RAB3GAP2, supporting a robust gene–disease association (PMID:29419336, PMID:32376645).
Genetic evidence derives from multiple families including a consanguineous Turkish pedigree with four affected siblings, where segregation analysis revealed the presence of a pathogenic allele in all affected individuals (PMID:29419336). In addition, other studies utilizing exome sequencing have identified compound heterozygous and homozygous RAB3GAP2 variants in individuals with Martsolf syndrome features, reinforcing the genetic linkage between RAB3GAP2 and the disease phenotype (PMID:32376645).
One representative variant reported is the in‐frame deletion, c.499_507del (p.Phe167_Thr169del), which has been identified in patients and is consistent with a hypomorphic effect. This variant, along with others, underlines the variable expressivity observed in the RAB3GAP2‐associated disease continuum. The observed variant spectrum includes splice site changes and missense variants that have been correlated with clinical severity gradients between Warburg Micro syndrome and the milder Martsolf syndrome presentation.
Functional studies have demonstrated that RAB3GAP2 mutations lead to impaired activity in the RAB3 cycle. Assays in patient‐derived cells and model systems confirm deficits in regulated exocytosis that align with the neurodevelopmental and ophthalmologic abnormalities of the syndrome (PMID:20967465). Although these data are primarily derived from models of Warburg Micro syndrome, they provide valuable insights into the pathogenic mechanisms underlying the Martsolf phenotype, particularly in cases with hypomorphic alleles.
The integration of robust genetic and functional data has resulted in a strong ClinGen gene–disease association for RAB3GAP2 with Martsolf syndrome. Multiple reports with segregation in consanguineous families, together with experimental evidence, support a causal link. This genetic information is essential for diagnostic decision-making and informs both clinical management and genetic counseling.
Key take‑home: The strong association between RAB3GAP2 mutations and Martsolf syndrome underlines the importance of comprehensive genetic testing in patients with congenital cataracts and developmental delay, facilitating precise diagnosis and improved patient care.
Gene–Disease AssociationStrongMultiple independent case reports and multi‐patient studies (e.g., 4 siblings in one consanguineous family [PMID:29419336] and additional cases in separate cohorts [PMID:32376645]) with segregation and functional data support a strong association. Genetic EvidenceStrongIdentification of pathogenic variants, including the in‐frame deletion c.499_507del (p.Phe167_Thr169del), in multiple probands with consistent Martsolf syndrome phenotypes supports a robust genetic contribution. Functional EvidenceModerateFunctional assays demonstrate reduced RAB3GAP2 activity and impaired RAB3 cycle regulation, aligning with the clinical features observed in Martsolf syndrome. |