Thrombocytopenia-absent radius (TAR) syndrome due to compound inheritance for a 1q21.1 microdeletion and a low-frequency noncoding RBM8A SNP: a new familial case

Abstract

BackgroundThrombocytopenia-absent radius syndrome (TAR; MIM 274000) is a rare autosomal recessive disorder combining specific skeletal abnormalities with a reduced platelet count. TAR syndrome has been associated with the compound inheritance of an interstitial microdeletion in 1q21.1 and a low frequency noncoding RBM8A SNP.ResultsHere, we report on a patient with scapulo-humeral hypoplasia, bilateral radio-ulnar agenesis with intact thumbs, bilateral proximal positioning of the first metacarpal, bilateral fifth finger clinodactyly, bilateral radial deviation of the hands, and thrombocytopenia. Molecular studies showed compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant in hemizygous state, inherited from the father and the mother, respectively. A second aborted fetus presented TAR features and 1q21.1 microdeletion.DiscussionThe complex inheritance pattern resulted in reduced expression of Y14, the protein encoded by RBM8A, and a component of the core exon-junction complex (EJC) in platelets. Further studies are needed to explain how Y14 insufficiency and subsequent defects of the EJC could cause the skeletal, haematological and additional features of TAR syndrome. In this study, we discuss other factors that could influence the overall phenotype of patients affected by TAR syndrome.ConclusionIn this study, we discuss other factors that could influence the overall phenotype of patients affected by TAR syndrome.

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

“…Targeted Sanger sequencing of the 5′ UTR of RBM8A (NM_005105.4; LRG_574t1) detected the known low-frequency SNV c.-21G>A, thereby establishing the molecular diagnosis of TAR syndrome. Compound heterozygosity of the microdeletion and a 5′ UTR SNV is the most common underlying genotype of TAR syndrome [ 3 , 4 , 6 , 12 , 15 , 16 , 17 ]. The parents were unavailable for segregation analysis, but the two variants detected in these siblings conforms to this common genotype, as does their classical presentation of TAR syndrome.…”

“…The RBM8A gene encodes the RNA-binding motif protein A, also designated the Y14 protein, which is a component of the exon junction complex (EJC), involved in numerous essential cellular functions [ 9 , 10 , 11 ]. Given this housekeeping role of the EJC, RBM8A is widely expressed, including in MGK and osteoblasts [ 9 , 10 , 12 , 13 ]. Functional studies have shown that Y14 levels are significantly lower in the PLTs of TAR syndrome patients, suggesting that here, RBM8A variants decrease protein expression to levels below a critical threshold [ 3 , 9 , 12 ].…”

“…Given this housekeeping role of the EJC, RBM8A is widely expressed, including in MGK and osteoblasts [ 9 , 10 , 12 , 13 ]. Functional studies have shown that Y14 levels are significantly lower in the PLTs of TAR syndrome patients, suggesting that here, RBM8A variants decrease protein expression to levels below a critical threshold [ 3 , 9 , 12 ].…”

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

“…All detected CNVs were tested for inheritance by hybridization of the parental DNA with the same array platform. De novo CNVs were confirmed either by FISH analysis or by quantitative real-time PCR as already reported (Vaccari et al, 2014;Tassano et al, 2015). To assess the clinical significance of the detected CNVs, we used several tools.…”

Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

“…Following the identification of the two SNPs, at least 22 new TAR cases have been reported (Omran et al , ; Bottillo et al , ; Baken et al , ; Idahosa et al , ; Papoulidis et al , ; Reid et al , ; Yassaee et al , ; Al Kaissi et al , ; Kumar et al , ,b; Pereira et al , ; Tassano et al , ; Nicchia et al , ; Jameson‐Lee et al , ). However, the presence of the microdeletion on chromosome 1q21.1 or of the hemizygous SNPs has not been reported in more than half of the described patients (Omran et al , ; Baken et al , ; Idahosa et al , ; Reid et al , ; Al Kaissi et al , ; Kumar et al , ; Pereira et al , ).…”