Thrombocytopenia Absent Radius (TAR) Syndrome via the RBM8A Gene - Sequencing and 1q21.1 Deletion

Thrombocytopenia with Absent Radius Syndrome (TAR) (CTRUS) is characterized by thrombocytopenia, bleeding diathesis, and absence of the radius with preservation of the thumb. Bleeding episodes associated with TAR tend to be moderate to severe after birth, but tend to diminish in frequency and severity over time. Skeletal abnormalities may extend to the absence of upper limbs and to the hips and knees (Greenhalgh et al. 2002). Absent radius combined with a blood phenotype is also a characteristic of Fanconi anemia (FA); FA can be distinguished from TAR by absence of the thumb in addition to the absent radius (Tischkowitz and Hodgson 2003; Dokal 2000). Other symptoms of TAR may include intolerance to cow’s milk, renal anomalies, and cardiac anomalies (Greenhalgh et al. 2002).

TAR does not appear to follow a typical autosomal dominant or recessive pattern of inheritance. Rather, the vast majority of patients with TAR have a compound inheritance that includes a null allele and a low frequency variant in the RBM8A gene. Most patients with TAR harbor a large deletion of chromosome 1q21.1, which includes the RBM8A gene (Klopocki et al. 2007; Papoulidis et al. 2014). Other reported null variants associated with TAR include a small insertion (c.207_208insAGCG) resulting in premature protein termination (p.Val70Serfs*3) (Albers et al. 2012) and a nonsense variant c.487C>T (p.Arg163*) (Albers et al. 2012). Paring one of these null alleles with one of two noncoding variants on the other allele, either c.-21G>A or c.67+32G>C, is strongly associated with disease; this combination of variants was found in 53 of 55 cases in one report with 51 cases having a large 1q21.1 deletion (Albers et al. 2012). This test includes sequencing of the coding regions of the RBM8A gene and sequencing for the c.-21G>A and c.67+32G>C variants along with a test for the large 1q21.1 deletion found in many TAR patients.

Due to the high frequency of the large 1q21.1 deletion in patients with TAR, we also offer separate individual deletion testing in addition to an individual RBM8A gene sequencing test.

In one study, 51 of 55 cases, or approximately 93% of Thrombocytopenia Absent Radius syndrome patients, were found to harbor one of two "functional polymorphisms" in the RBM8A gene (either c.-21G>A or c.67+32G>C) in combination with a large 1q21.1 deletion that includes the RBM8A gene (Albers et al 2012). An additional 2 patients were found to harbor one of the two functional polymorphisms in combination with a null allele other than the large 1q21.1 deletion.   

This test includes sequencing of the RBM8A gene AND a test for the large 1q21.1 deletion found in many TAR patients. We sequence the full coding region of the RBM8A gene plus ~10 bp of non-coding DNA flanking each exon using Sanger sequencing. We also include in this test sequencing for the c.-21G>A and c.67+32G>C variants detailed above. This test provides 100% coverage of the RBM8A gene. Testing for the 1q21.1 deletion includes analysis of only the RBM8A gene using our high density chromosomal microarray (CMA). We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Testing for sequence variants in the RBM8A gene and for the large 1q21.1 deletion is recommended if the index of suspicion for TAR is high.