RBM10 is an X-linked gene, and loss-of-function variants, especially nonsense and frameshift variants, have been traditionally associated with TARP syndrome only in males. More recently, a larger deletion encompassing the RBM10 gene has also been implicated as causing TARP syndrome in a male infant. Splicing variants have also been linked to TARP syndrome, though considering the milder presentation in these boys, it is possible that such variants are hypomorphic and lead to decreased production of RBM10 protein rather than complete loss. However, some individuals with milder phenotypes (Gripp et al. 2011) also have nonsense or frameshift variants, invoking the possibility of phenotypic modifiers or alternative mechanisms for explaining variable expressivity. Højland et al. were the first to describe an adult individual with TARP syndrome. Molecular analysis in this individual detected a frameshift variant in exon 4, which is variably included or spliced in different RBM10 transcripts so they speculated that this might explain a less severe presentation. Finally, large population databases indicate that RBM10 is both loss intolerant and missense depleted in the general population, and there is growing evidence for an RBM10-related condition (generally milder than the classic TARP syndrome presentation) in individuals with certain missense and partial gene in-frame deletions of RBM10 (Wang et al. 2013).
RBM10