Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA geneRNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome.Objective:
We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants inRNU4ATACto gain insight into the mechanisms behind this disorder.Methods:
We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages.Results:
The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor–dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, includingDIAPH1andHPS1, genes known to regulate platelet and dense granule formation, respectively.Conclusion:
Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome.