Disorders associated with TBC1D20 mutations are recessive. Thus, an affected individual has both copies of the TBC1D20 gene mutated. In the same individual, the two mutations are generally identical (homozygosis), due to parental consanguineity. To date, seven different mutations of the TBC1D20 gene have been described. For mutations related to Warburg micro syndrome, the most accredited mechanism through which these mutations alter the function of the gene is loss of function due to loss of gene expression. It is hypothed that for mutations that cause Martsolf syndrome, the consequences on protein expression/function are milder, with the mutated protein maintaining a minimal residual activity.
Since TBC1D20 mutations are different from family to family, the genetic test that is used to detectd TBC1D20 mutations is sequencing of the entire gene. Because Warburg micro syndrome and Martsolf syndrome are also caused by mutations in three other genes (RAB3GAP1, RAB3GAP2 and RAB18), and patients with the mutation in these other genes are clinically indistinguishable from those with mutations in TBC1D20, the molecular diagnosis involves parallel sequencing of a panel including all Warburg micro syndrome/Martsolf syndrome causative genes (RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20). Since large deletions have been described in TBC1D20 and other Warburg micro syndrome/Martsolf syndrome genes, in those cases where biallelic point variants have not been identified, the application of a method capable of detecting intragenic deletions and duplications in these genes is recommended, e.g., quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and/or gene-targeting microarrays designed to detect single exon deletions or duplications. If this approach is also negative, extending mutation analysis to the whole exome and/or whole genome is appropriate because more than 40% of cases with Warburg micro syndrome/Martsolf syndrome do not have mutations in known genes.
TBC1D20