Warburg Micro Syndrome 2

A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-2 (WARBM2) is caused by homozygous mutation in the RAB3GAP2 gene (609275) on chromosome 1q41.

Martsolf syndrome (212720), a clinically overlapping but milder disorder, is also caused by mutation in the RAB3GAP2 gene.

For a general phenotypic description and a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118.

Clinical Features

Borck et al. (2011) reported a girl from a consanguineous Turkish family with Warburg Micro syndrome who presented with congenital cataracts, microphthalmia, absent visual evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay.

Molecular Genetics

In a girl from a consanguineous Turkish family with Warburg Micro syndrome, Borck et al. (2011) identified homozygosity for a small in-frame deletion in the RAB3GAP2 gene (609275.0002). The parents were heterozygous carriers of the mutation, which was not found in 188 Turkish and 170 German control chromosomes. Analysis of RAB3GAP2 in 10 additional unrelated children with suspected Warburg Micro syndrome who were negative for mutation in the RAB3GAP1 (602536) gene revealed no further mutations.

In affected individuals from 7 families with the typical features of Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for mutations in the RAB3GAP2 gene (see, e.g., 609275.0004-609275.0006).

Genotype/Phenotype Correlations

Handley et al. (2013) reviewed brain MRI findings in 17 patients with mutations in the RAB3GAP1, RAB3GAP2, and RAB18 (602207) genes. While brain findings were remarkably similar among the patients, the overall impression was of a relatively milder brain phenotype in the 9 patients with mutations in RAB3GAP2, with frontal polymicrogyria mostly not extending beyond the perisylvian fissure to the temporal and occipital lobes, no apparent white matter loss, and no cerebellar or cerebellar vermis hypoplasia.