Mutation Spectrum inRAB3 GAP1,RAB3 GAP2, andRAB18and Genotype-Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome


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Abstract

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified invelopmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified inRAB3GAP1, RAB3GAP2,orRAB18,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 families and 52 new families. Onehundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations inRAB3GAP1in 41% of cases, mutations inRAB3GAP2in 7% of cases, and mutations inRAB18in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS 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 MS.deleterious mutations causing Micro syndrome and milder mutations causing MS.RAB18has not yet been linked to the RAB3 pathways, butmutations 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.

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