Long-read sequencing unravels the complexity of structural variants in PRKN in two individuals with early-onset Parkinson's disease

BackgroundPRKN biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinsons disease (PD). However, the variants responsible for suspected PRKN-PD individuals are not always identified with standard genetic testing. ObjectivesIdentify the genetic cause in two siblings with a PRKN-PD phenotype using long-read sequencing (LRS). MethodsThe genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger sequencing, targeted sequencing, whole-exome sequencing and LRS. ResultsMLPA and targeted sequencing identified one copy of exon four in PRKN but no other variants were identified. Subsequently, LRS unveiled a large deletion encompassing exon 3 to 4 on one allele and a duplication of exon 3 on the second allele; explaining the siblings phenotype. MLPA could not identify the balanced rearrangement of exon 3. ConclusionsThis study highlights the potential utility of long-read sequencing in the context of unsolved typical PRKN-PD individuals.