TBC1D20 gene encodes a RAB-GAP protein with modest GAP activity towards the RAB18 protein. Proper functioning of TBC1D20 is required for proper functioning of RAB18, the absence or malfunction of which causes Warburg micro syndrome and Martsolf syndrome.
Mutations in the TBC1D20 gene are recessive and all described individuals are homozygous, due to parental consanguinity. So far, seven families have been reported. Six of these were affected by Warburg micro syndrome and one by Martsolf syndrome.
Reported mutations include four different nonsense variants identified in five independent families, four of which with Warburg micro syndrome and one with Martsolf syndrome, one frameshift variant and one multiexonic deletion identified in two patients affected by Warburg micro syndrome. The likely pathogenic mechanism of these variant 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.
Diagnosis/testing
Because of the genetic heterogeneity and clinical overlap that characterize Warburg micro syndrome and Martsolf syndrome, molecular diagnosis involves parallel sequencing of a panel that includes all the genes so far associated with the two conditions (RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20). Since intragenic deletions have been described in TBC1D20 and other Warburg microsyndrome/Martsolf syndrome genes, in cases where biallelic point variants have not been identified by targeted panel resequencing it is recommended to extend the analysis to intragenic deletions and duplications in the same genes using quantitative methods designed to detect these gene anomalies, such as quantitative PCR, long-range PCR, multiplex-ligation-dependent probe amplification (MLPA), and/or gene-targeting microarrays. If this approach is also negative, sequencing analysis of the whole-exome and/or whole-genome could be taken into consideration because more than 40% of cases with Warburg micro syndrome/Martsolf syndrome do not have mutations in known genes.
