RBM8A compound heterozygosity causes a complete TAR phenotype in 3 siblings from two pedigrees: a novel frameshift RBM8A variant, focus on the orthopedic involvement, and review of literature on compound heterozygous patients

Background Thrombocytopenia with Absent Radii (TAR) syndrome is a rare congenital disorder caused by compound inheritance of a hypomorphic non-coding variant and a null allele of RBM8A . In most patients, the null allele corresponds to a recurrent 1q21.1 microdeletion encompassing RBM8A and adjacent genes, whereas cases due to RBM8A null point pathogenic variants are rarer so that the clinical spectrum associated with non-deletional RBM8A defects remains still poorly characterized. Methods We report three patients with TAR syndrome from two unrelated families carrying compound heterozygosity for hypomorphic and null RBM8A variants. Clinical, hematological and orthopedic data were collected. A narrative review of previously published TAR patients with RBM8A null point variants in trans with hypomorphic alleles was performed. Results All patients displayed a complete TAR phenotype, including thrombocytopenia and bilateral radial agenesis with thumb preservation. In one family, a novel frameshift RBM8A variant (c.78_91del14; p.His26Glnfs*22) was identified, expanding the mutational spectrum of the gene. Review of published cases confirmed that compound heterozygosity for RBM8A null variants is sufficient to cause the full TAR phenotype. Notably, one pediatric patient showed severe knee abnormalities, including hypoplastic patella and trochlear dysplasia, documented by X-ray and MRI. Conclusions Our findings confirm that RBM8A haploinsufficiency alone is sufficient to determine the complete TAR phenotype and highlight under-recognized orthopedic manifestations, particularly involving the knee. Comprehensive molecular and orthopedic evaluation should be considered in patients with non-deletional RBM8A -related TAR syndrome.