Mutation spectrum in RAB3GAP1, RAB3GAP2 and RAB18 and Genotype-Phenotype Correlations in Warburg Micro syndrome and Martsolf syndrome

Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2 or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published and 52 new families. 144 Micro and 9 Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases and in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases (LOVD) we created for all 3 genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotype in Micro and Martsolf syndromes represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes with more deleterious mutations causing Micro syndrome and milder mutations causing Martsolf syndrome. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.