Warburg Micro Syndrome via the RAB3GAP1 Gene

Warburg micro syndrome is an autosomal recessive disorder characterized by ocular, neurologic and endocrine abnormalities. Initial clinical findings are typically ocular and include bilateral congenital cataracts, microphthalmia, microcornea, and atonic pupils. Brain malformations are often seen on MRI and include polymicrogyria (primarily of the frontal and parietal lobes), cortical atrophy, and hypogenesis of the corpus callosum. Other key findings include severe intellectual disability, optic nerve atrophy, cortical visual impairment, postnatal microcephaly (rarely congenital), short stature, and hypogonadism (Handley et al. 2012. PubMed ID: 23176487; Handley et al. 2013. PubMed ID: 23420520; Handley and Sheridan 2018. PubMed ID: 29300443).

Martsolf syndrome has many overlapping features with Warburg micro syndrome but is considered to be less severe, often with milder intellectual disability and microcephaly while lacking optic atrophy and cortical visual impairment (Handley et al. 2012. PubMed ID: 23176487). Warburg micro and Martsolf syndromes were initially considered to be distinct; however, following the discovery of the molecular causes of each it is now believed these two disorders represent opposite ends of the same clinical spectrum.

Warburg micro syndrome is an autosomal recessive disorder with pathogenic variants described in four genes (RAB3GAP1, RAB3GAP2, RAB18, TBC1D20). The majority of individuals with Warburg micro syndrome have pathogenic variants in RAB3GAP1 (41%), followed by RAB3GAP2 (7%), RAB18 (5%) and TBC1D20 (~5-6%) (Handley et al. 2012. PubMed ID: 23176487; Liegel et al. 2013. PubMed ID: 24239381).

To date, approximately 60 pathogenic variants have been reported in RAB3GAP1 with nearly all being likely loss of function pathogenic variants (nonsense, splicing, frameshift, large deletions). Only three missense variants have been reported; however, Gerondopoulos and colleagues reported that two of these are also likely loss of function as they result in no RAB3GAP1 GEF activity (Gerondopoulos et al. 2014. PubMed ID: 24891604).

RAB18 is a member of the RAB family of the RAS superfamily of small GTPases. RAB18 is involved in a number of different intracellular trafficking processes. The activity of RAB18 is dependent upon its GTP/GDP bound state. This state is regulated by GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins). RAB3GAP, which consists of RAB3GAP1 and RAB3GAP2 subunits, has been shown to act as a GAP specific for RAB3 proteins; however, until recently the relationship between RAB18 and RAB3GAP was unknown. Recent data suggest that contrary to its name the RAB3GAP complex can also act as a GEF specific for RAB18 (Gerondopoulos et al. 2014. PubMed ID: 24891604).

Pathogenic variants in RAB3GAP1 were found in 63/153 (41%) families with Warburg micro syndrome or Martsolf syndrome (Handley et al. 2013. PubMed ID: 23420520).

This test provides full coverage of all coding exons of the RAB3GAP1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).