Warburg Micro Syndrome Panel

Warburg Micro syndrome (WMS) is a rare autosomal recessive disorder with brain, eye, and endocrine abnormalities. WMS is characterized by congenital microcephaly, cortical dysplasia, agenesis or hypoplasia of the corpus callosum, microphthalmia, microcornea, congenital cataracts, optic atrophy, profound intellectual disability, and hypogenitalism (Derbent et al. 2004; Graham et al. 2004; Handley et al. 2013).

WMS may be distinguished from other similar clinical disorders such as Cerebro-Oculo-Facio-Skeletal syndrome and Cockayne syndrome by normal nucleotide excision repair (NER) in cultured fibroblasts. It is also distinguished by the presence of significant visual abnormalities, frontal polymicrogyria, thin corpus callosum, and cortical atrophy by MRI. The most difficult differential diagnosis would be between WMS and Martsolf syndrome (MS). MS syndrome patients have a higher life expectancy, and MS is considered milder than WMS (Morris-Rosendahl et al. 2010).

WMS is a heterogeneous disorder; however, the gene involved cannot be ascertained based on clinical phenotype (Handley et al. 2013; Liegel et al. 2013).

WMS is an autosomal recessive disorder associated with causative variants in four genes: RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20. MS has been associated with pathogenic variants in RAB3GAP2. Together, pathogenic variants in these genes account for about 50% of WMS and MS cases. Rabs are small G proteins of the Ras superfamily, which are involved in vesicular trafficking. RAB3GAP, which regulates Rab3 activity, is a heterodimeric complex consisting of a catalytic subunit encoded by RAB3GAP1 and a noncatalytic subunit encoded by RAB3GAP2. RAB18 encoded protein is mostly localized to lipid droplets and has a role in lipid dynamics and lipid storage activities. However, its relationship to RAB3GAP1 and RAB3GAP2 has not been investigated (Martin et al. 2005; Handley et al. 2013). Recently, TBC1D20, which is a RabGTPase-activating protein, has shown to be associated with WMS (Liegel et al. 2013).

So far ~50 pathogenic variants in RAB3GAP1 (truncating mutations, missense, splicing, small and gross deletions); ~10 pathogenic variants in RAB3GAP2 (truncating mutations, missense, splicing, small deletions and insertions), ~5 pathogenic variants in RAB18 (missense, nonsense, small and gross deletions) and ~5 pathogenic variants in TBC1D20 (nonsense, small and gross deletions) have been reported that are associated with WMS and MS (Human Gene Mutation Database).

See individual gene test descriptions for more information on molecular biology of gene products.

In a study that investigated 153 families (144 WMS and 9 MS patients), pathogenic variants were identified in RAB3GAP1 (41% of cases), RAB3GAP2 (7% of cases), and RAB18 (5% of cases) (Handley et al. 2013). Sequence analysis of 77 families affected by WMS (negative for RAB3GAP1, RAB3GAP2, and RAB18 pathogenic variants), found seven individuals found to be homozygous for TBC1D20 pathogenic variants (Liegel et al. 2013).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).