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

Abstract

Background: PRKN biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinson's disease (PD). However, the variants responsible for suspected PRKN- PD individuals are not always identified with standard genetic testing.

Objectives: Identify the genetic cause in two siblings with a PRKN -PD phenotype using long-read sequencing (LRS).

Methods: The genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger sequencing, targeted sequencing, whole-exome sequencing and LRS.

Results: MLPA 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.

Conclusions: This study highlights the potential utility of long-read sequencing in the context of unsolved typical PRKN- PD individuals.