Long-Read Sequencing Unravels the Complexity of Structural Variants in PRKN in Two Individuals with Early-Onset Parkinson’s Disease

About 5% to 10% of Parkinson's disease (PD) cases are monogenic; otherwise PD is generally known to be idiopathic. Although more than a dozen genes that contain disease-causing mutations have been identified to date, PRKN is the most frequently mutated gene in autosomal recessive early-onset PD (EOPD). However, the genetic cause of patients with a typical PRKN phenotype is sometimes elusive because of the limitations of traditional genetic methods to detect complex structural mutations that are frequent in PRKN. The phenotype is usually specific, consisting of a slowly progressive EOPD with a good and long-standing response to levodopa. Dystonia, dyskinesia, and motor fluctuations are typical, whereas autonomic dysfunction, psychotic symptoms, and cognitive decline are usually absent. We report 2 siblings of European ancestries exhibiting PRKN phenotype left undiagnosed for years after multiple genetic investigations.