Mutation Spectrum inRAB3GAP1,RAB3GAP2, andRAB18and Genotype-Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome

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 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 families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 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. 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.

Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy

“…This is especially the case given that mutations in the RAB3GAP1 gene associated with WARBM1 were described in families of very varied ethnic origin, with the number of mutations identified already exceeding 50 [14]. The clinical picture of the WARBM1 in our patients corresponds with the phenotype described by other authors [7]. However, not typically, in our patients peripheral demyelinating motor-sensory polyneuropathy and cardiomyopathy were identified.…”

Genetics and mechanisms leading to human cortical malformations

“…The most severe outcomes of PMG occur in children with severe microcephaly (-3 SD or smaller). Patients with severe congenital microcephaly and PMG have for example, shown mutations in WDR62 (WD repeat-containing protein 62), NDE1, RTNN and RAB3GAP1/2 and RAB18 [240][241][242]. PMG with microcephaly or normal brain size, corpus callosum dysgenesis and cerebellar hypoplasia may also be related to tubulin and MT-motor gene mutations such as KIF1B binding protein, TUBA1A, TUBB, TUBB2B, TUBB3, and DYNC1H1 (see Tables 1 and 2) [156,199,237].…”

Targeted disruption of Tbc1d20 with zinc-finger nucleases causes cataracts and testicular abnormalities in mice

“…Warburg Micro syndrome (WARBM) is a genetically heterogeneous autosomal recessive syndromic disorder characterized by eye, brain, and genital abnormalities [1]. Mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes cause WARBM1, WARBM2, WARBM3, and WARBM4 forms respectively [2][3][4][5].…”

“…Mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes cause WARBM1, WARBM2, WARBM3, and WARBM4 forms respectively [2][3][4][5]. Regardless which of the four genes harbors the causative mutation, all WARBM individuals present with indistinguishable clinical features [1,5]. Eye abnormalities in WARBM children are characterized by congenital cataracts, microphakia, microcornea, microphthalmia, optic nerve atrophy, and small, atonic pupils [6,7].…”

“…Postnatal microcephaly, predominantly frontal polymicrogyria, corpus callosum hypogenesis, enlarged subdural spaces, cerebellar vermis hypoplasia are brain characteristics in the affected WARBM children; these abnormalities are accompanied by seizures and severe intellectual disability [8][9][10]. Microgentialia is present in both the WARBM affected boys and girls [1,7,9]. In addition to eye, brain and genital abnormalities, WARBM children also exhibit hypotonia of truncal muscles, as well as spasticity of the limbs resulting in the inability to walk, sit, or crawl, and ultimately resulting in quadriplegia [1].…”