Genome and transcriptome sequencing reveal pathogenic activation of a pseudoexon in

Purpose: Despite improvements in and access to clinical genetic testing, many patients with classic phenotypes remain without a molecular diagnosis. Such cases may reflect variants in noncoding regions or complex alleles made up of disparate sequence variants. In this article, we report a patient with autosomal dominant polycystic kidney disease caused by a deep intronic de novo single-nucleotide substitution forming a dinucleotide variant, with an adjacent common single-nucleotide variant (formerly single-nucleotide polymorphism) inherited from an unaffected parent. Although neither variant alone was predicted to be pathogenic, together as a dinucleotide variant, they created a novel splice donor site that activated a pseudoexon within intron 16 of the Methods: Genome sequencing was paired with transcriptome sequencing to evaluate the dinucleotide variant within intron 16 of Results: Evaluation of RNA from patient cells confirmed the inclusion of a 114-bp pseudoexon and an in-frame premature termination codon into the Conclusion: This case highlights the diagnostic utility of genome sequencing coupled with RNA sequencing to clarify the effects of a deep intronic variant, confirming a molecular diagnosis for a patient with a clear clinical diagnosis who had undergone years of inconclusive testing. Furthermore, this case cautions that similar events may underlie unsolved cases across other genes and disorders.