In vitro pathogenicity evaluation of deep intronic variants for recessive genetic retinal diseases
Non-coding variants altering mRNA splicing are increasingly recognized as important cause of Mendelian disorders. Deep intronic variants (DIV) that activate cryptic exons (CEs) cause ~20% inherited retinal diseases (IRD) cases, yet it remains challenging to predict intronic variant pathogenicity accurately, thus we used a high throughput splicing assay (HTSA) to measure the effects of rare deep…
Recent research has shed light on the role of non-coding variants in causing Mendelian disorders, particularly inherited retinal diseases (IRD). A study utilized a high-throughput splicing assay (HTSA) to evaluate the pathogenicity of deep intronic variants (DIV) in recessive IRDs. 640 rare DIVs were selected and tested, with 98 variants found to activate cryptic exons (CEs) 100 times more than the reference sequence, classifying them as pathogenic.
Additionally, 26 variants were classified as VUS. However, only 6 out of 90 variants (6,6%) were predicted to be pathogenic by in silico algorithms like Splice AI, highlighting the need for improvement in prediction algorithms. The findings confirmed diagnoses for 50 out of 78 patients (64%), indicating that 19.4% of deep intronic variants cause CEs activation, potentially implicating a significant portion of undiagnosed patients with recessive IRDs carrying pathogenic intronic mutations.
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