Thrombocytopenia-Absent Radius Syndrome: Descriptions of Three New Cases and a Novel Splicing Variant in RBM8A That Expands the Spectrum of Null Alleles

Abstract

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G>A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G>A (hypomorphic allele) and a novel pathogenic variant, c.343-2A>G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.

Keywords: 1q21 microdeletion; RBM8A; neonatal thrombocytopenia; null allele; thrombocytopenia-absent radius (TAR) syndrome.

Figure 1

(a) Amplification products of RBM8A cDNA exons 2 to 6 (F2-II.1.) The control sample (C) shows a normal-sized fragment (~460 bp), as expected for the region encompassing exons 2 to 6. The patient (P) presents a faint, normal-sized fragment and a predominantly shorter fragment (~320 bp), consistent with the absence of exon 5. The residual intermediate-sized fragment reflects heteroduplex formation (verified by Sanger sequencing; data not shown). (b) Partial electropherograms showing the exon 4/exon 6 junction sequence in the patient’s aberrant fragment and the normal exon 4/exon 5 junction sequence in the control. M—size markers: GeneRuler 100 bp Plus DNA ladder (Thermo Fisher Scientific, Waltham, MA, USA).

Figure 2

(a) Schematic representation of the RBM8A gene and the localization of TAR syndrome associated variants classified as pathogenic/likely pathogenic, as documented in the literature. The novel variant identified in this work is highlighted in a box. The nomenclature is used according to HGVS, using Reference Sequence NM_005105.4, LRG_574t1. When available, frequencies in the gnomAD database and dbSNP identification references are shown. Blue boxes—exons; grey boxes—UTRs; RRM—RNA recognition motif; VUS—variant of uncertain significance. (b) Summary of documented TAR syndrome genotypes and known/predicted effects of the variants. NMD—nonsense-mediated mRNA decay. Source [2,3,6,8,12,15,16,17,18,19,20,21,22,23,24,25,26].