1q21.1 deletion and a rare functional polymorphism in siblings with thrombocytopenia-absent radius–like phenotypes

Abstract

Thrombocytopenia-absent radii (TAR) syndrome, characterized by neonatal thrombocytopenia and bilateral radial aplasia with thumbs present, is typically caused by the inheritance of a 1q21.1 deletion and a single-nucelotide polymorphism in RBM8A on the nondeleted allele. We evaluated two siblings with TAR-like dysmorphology but lacking thrombocytopenia in infancy. Family NCI-107 participated in an IRB-approved cohort study and underwent comprehensive clinical and genomic evaluations, including aCGH, whole-exome, whole-genome, and targeted sequencing. Gene expression assays and electromobility shift assays (EMSAs) were performed to evaluate the variant of interest. The previously identified TAR-associated 1q21.1 deletion was present in the affected siblings and one healthy parent. Multiple sequencing approaches did not identify previously described TAR-associated SNPs or mutations in relevant genes. We discovered rs61746197 A > G heterozygosity in the parent without the deletion and apparent hemizygosity in both siblings. rs61746197 A > G overlaps a RelA–p65 binding motif, and EMSAs indicate the A allele has higher transcription factor binding efficiency than the G allele. Stimulation of K562 cells to induce megakaryocyte differentiation abrogated the shift of both reference and alternative probes. The 1q21.1 TAR-associated deletion in combination with the G variant of rs61746197 on the nondeleted allele is associated with a TAR-like phenotype. rs61746197 G could be a functional enhancer/repressor element, but more studies are required to identify the specific factor(s) responsible. Overall, our findings suggest a role of rs61746197 A > G and human disease in the setting of a 1q21.1 deletion on the other chromosome.

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

“…Thrombocytopenia-absent radius is a syndromic bleeding disorder characterized by low PLT counts in association with the bilateral absence of the radii. Previous work has shown that TAR syndrome is a complex genetic disorder caused by the compound inheritance of a rare null allele and a low frequency hypomorphic noncoding variant in the RBM8A gene [ 3 , 7 , 8 , 18 ]. It was demonstrated that this combination, where one copy of the gene is absent or non-functional and the expression of the other allele is downregulated, culminates in the diminished expression of the encoded Y14 protein, which is a constituent of the EJC [ 3 , 4 , 7 , 8 ].…”

“…The modifying allele remained elusive until 2012, when Albers et al first described the involvement of low-frequency single nucleotide variants (SNVs) in the regulatory regions of the RBM8A gene [ 7 ]. Together with the 1q21.1 microdeletion, most patients carried either the noncoding SNV c.-21G>A in the 5′ untranslated region (UTR) or the intronic SNV c.67+32G>C. Moreover, two patients without the microdeletion were found to carry the RBM8A 5′UTR SNV and an allelic loss-of-function variant (c.207_208insAGCG or c.487C>T).…”

“…Together with the 1q21.1 microdeletion, most patients carried either the noncoding SNV c.-21G>A in the 5′ untranslated region (UTR) or the intronic SNV c.67+32G>C. Moreover, two patients without the microdeletion were found to carry the RBM8A 5′UTR SNV and an allelic loss-of-function variant (c.207_208insAGCG or c.487C>T). These data suggested that the genetic basis of TAR syndrome is compound heterozygosity for a noncoding, hypomorphic SNV and a rare null allele, both involving RBM8A [ 3 , 7 ]. Recently, Boussion et al described four other pathogenic RBM8A variants amongst a cohort of 26 patients [ 8 ].…”

Thrombocytopenia Absent Radius (TAR)-Syndrome: From Current Genetics to Patient Self-Empowerment

“…Additionally, several other SNPs have been reported. [11][12][13] In 75% of TAR cases, the microdeletion is inherited from one parent, whereas in about 25% of cases the microdeletion occurs de novo. In case that the carrier status of both parents is known, there is a recurrence risk of 25% in every pregnancy for a child with TAR syndrome as in autosomal recessive disorders.…”

“…When the microdeletion occurred de novo, the risk will rather be 1:100,000. Of note, some rare null mutations of RBM8A have been reported in patients without a microdeletion 9,[11][12][13] (►Fig. 2), expanding the list of variant combinations underlying this disorder (►Table 1).…”