No abstract

Variants that perturb splicing are major contributors to disease. Recent evidence implicate non-canonical intronic variants as a poorly characterized yet highly prevalent class of alterations associated with Mendelian disorders. Here, we report the first detailed RNA expression and splicing analysis from a large family with an intronic RPL11 variant associated with Diamond Blackfan Anemia (DBA). DBA manifests with incomplete penetrance and partial expressivity yet the mechanism of this variability remains enigmatic. Our analysis revealed a complex pattern of disruptions with many novel junctions of RPL11. These include an RPL11 transcript that is translated with a late stop codon in the 3' untranslated region (3'UTR) of the main isoform and an antisense exon-exon junction variant present only in carriers. We observed that RPL11 transcript abundance is comparable among carriers regardless of symptom severity. In contrast, both the small and large ribosomal subunit transcripts were significantly overexpressed in individuals with more prominent DBA symptoms. Finally, we discovered that coordinated expression between mitochondrial components and RPL11 was lost in all carriers, which may lead to variable expressivity. Overall, this study highlights the importance of RNA splicing and expression analyses in families for molecular characterization of Mendelian diseases.