RBM8A was first reported in relation to autosomal recessive thrombocytopenia-absent radius syndrome (TAR) in 2007 (Klopocki E, et al., 2007, PMID: 17236129) when a heterozygous 1q21.1 microdeletion was associated with the syndrome. In 2012 (Albers CA, et al., 2012, PMID: 22366785) the mechanism was clarified as compound inheritance of a null mutation and a low frequency regulatory SNP. The null allele in the vast majority of cases is a 1q21.1 microdeletion spanning at least 200kb and including at least 12 genes in addition to RBM8A. Seventeen additional genes commonly included in these deletions (NBPF10, HJV, TXNIP, POLR3GL, ANKRD34A, LIX1L, GNRHR3, PEX11B, ITGA11, ANKRD36, PIAS4, NUD18, POLR3C, RNF115, CD160, PDZK1, and GPR89A) have been evaluated to assess the impact of the loss of the additional material and found to have no known association with TAR, based on lack of associated coding sequence mutations (via candidate gene sequencing in PMID: 17236129 and exome sequencing in PMID: 22366785), or the predominant phenotypes of bilateral radial aplasia and thrombocytopenia, based on associations reported in OMIM or ORPHANET and a literature review. Additionally, four cases of TAR with non-deletion RBM8A null alleles strengthen the evidence that RBM8A is the associated gene within the 1q21.1 deletion (PMIDs: 22366785, 32227665).
In addition to the 1q21.1 deletion alleles, at least 9 unique variants (1 frameshift, 1 nonsense, 2 splicing, and 5 regulatory SNPs located in the 5’UTR, first intron, or 3’UTR) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands, where both variants have been described, in 8 publications (PMIDs: 22366785, 24053387, 32227665, 32109542, 24220582, 26550033, 32127157, 28690869). Variants in this gene segregated with disease in 3 additional family members. This gene-disease relationship is supported by the expression of RBM8A in relevant tissues, the functional alteration in megakaryocytopoiesis of patient cells (PMID: 10688818), and some phenotypic consistency with animal models (PMIDs: 22366785, 11696323, 25948253). In summary, RBM8A is definitively associated with autosomal recessive TAR.
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