Genome and Transcriptome Sequencing Reveal Pathogenic Activation of a Pseudoexon in PKD1 via a de novo–Common Variant Complex Allele

Despite improvements and access to clinical genetic testing, many patients with classic phenotypes remain without a molecular diagnosis. Such cases may reflect variants in non-coding regions or complex alleles made up of disparate sequence variants. 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 SNP inherited from an unaffected parent. While 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 PKD1 gene.