Genotype-Phenotype Correlation in RBM10-Associated Syndromes. How Variant Function Shapes a Broad Phenotypic Landscape

Abstract

Severe loss of function variants in the splicing regulatory protein RBM10 are known to cause TARP syndrome, a rare X-linked recessive congenital syndrome. In recent years, individuals with milder phenotypes have been published, suggesting a broader phenotypic spectrum. We report 37 new individuals with RBM10 variants and compare to 34 published cases. We find that the phenotype can be described as an "RBM10-phenotypic spectrum" which can be further subdivided into two phenotypic groups, TARP syndrome (TARPS) and RBM10 Associated Intellectual Disability (RAID). Based on phenotype characterizations and functional studies, we describe a clear genotype-phenotype correlation. Splicing analysis of blood samples and CRISPR-edited cells representing different degrees of functional loss of RBM10 demonstrated a pattern of more exon inclusion in response to increased loss of RBM10 function. More inclusion was correlated with increasing phenotype severity. Functional studies of missense variants from the different phenotypic groups confirm this genotype-phenotype correlation and show that different molecular mechanisms can explain the underlying pathological alterations in RBM10 protein function. Interestingly, we show that some missense variants in the RNA binding, RRM2 domain of RBM10 alter RBM10 activity from splicing inhibition to stimulation, likely due to altered RNA binding characteristics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/25330579v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@555538org.highwire.dtl.DTLVardef@4e0c39org.highwire.dtl.DTLVardef@4a187org.highwire.dtl.DTLVardef@8aa2d_HPS_FORMAT_FIGEXP M_FIG C_FIG