RBM8A – Thrombocytopenia-Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is a rare autosomal recessive disorder characterized by neonatal thrombocytopenia and bilateral absence of the radial bones with preserved thumbs. Patients typically present in infancy with life-threatening bleeding due to reduced platelet counts and radial ray defects detected on prenatal ultrasound or postnatal radiography. Most affected individuals are compound heterozygotes for a heterozygous 1q21.1 microdeletion encompassing RBM8A and a hypomorphic noncoding variant in the remaining allele, establishing an obligate biallelic inheritance mechanism.

Genetic analyses across 55 unrelated probands confirmed compound inheritance in 53 cases, including 51 carrying the 1q21.1 deletion and two with null RBM8A alleles, and two cases with truncating variants, supporting a definitive gene–disease relationship (PMID:22366785). Segregation in multiple families, including an affected sib pair and prenatal recurrence, further corroborates autosomal recessive transmission. A spectrum of RBM8A variants comprises hypomorphic regulatory SNVs (c.-21G>A, rs139428292; c.67+32G>C), splicing mutations (c.343-2A>G), null frameshift and nonsense alleles such as c.487C>T (p.Arg163Ter), and multi-kb deletions.

Hypomorphic alleles in the 5′UTR or intronic regions reduce RBM8A transcript levels, whereas null alleles abolish Y14 protein expression. In vitro reporter assays demonstrated that both rs139428292 and rs201779890 decrease promoter activity, and quantitative RT-PCR confirmed hemizygous expression in probands. NGS approaches reliably detect the dual hit of copy-number and SNV alterations in RBM8A, streamlining molecular diagnosis (PMID:27320760, PMID:32227665).

Functional studies revealed diminished Y14 protein levels in platelets from TAR patients and loss of EJC integrity. Mouse models heterozygous for Rbm8a recapitulate neurodevelopmental defects via p53-mediated apoptosis, underscoring the dosage sensitivity of EJC components and the mechanism of haploinsufficiency (PMID:27618312). Electrophoretic mobility shift assays in patient-derived lymphoblasts suggested altered transcription factor binding at regulatory SNPs, providing molecular insight into noncoding variant pathogenicity.

A disputed report described two siblings with bilateral radial aplasia but lacking thrombocytopenia, linked to a 1q21.1 deletion and a novel enhancer-region SNP, suggesting potential phenotypic modifiers or incomplete penetrance (PMID:31836590). However, the core hematological and skeletal features remain robustly associated with RBM8A insufficiency.

Integration of genetic and functional data yields a definitive ClinGen classification. Comprehensive detection of both deletion and noncoding variants in RBM8A is essential for accurate diagnosis, prenatal counseling, and informed management of TAR syndrome. Key Take-home: Biallelic alteration of RBM8A underlies TAR syndrome, and combined CNV plus SNV testing optimizes molecular diagnosis and genetic counseling.

References

• Nature genetics • 2012 • Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome PMID:22366785
• Human mutation • 2020 • TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A. PMID:32227665
• PLoS genetics • 2016 • Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly. PMID:27618312
• Cold Spring Harbor molecular case studies • 2019 • 1q21.1 deletion and a rare functional polymorphism in siblings with thrombocytopenia-absent radius-like phenotypes. PMID:31836590

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