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

• Published in: Movement disorders Vol. 39; no. 9; pp. 1647 - 1648
• Main Authors: Cogan, Guillaume, Daida, Kensuke, Billingsley, Kimberley J., Tesson, Christelle, Forlani, Sylvie, Jornea, Ludmila, Arnaud, Lionel, Tissier, Laurène, LeGuern, Eric, Singleton, Andrew B., Ferrien, Mélanie, Bernard, Hélène Gervais, Lesage, Suzanne, Blauwendraat, Cornelis, Brice, Alexis
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.09.2024; Wiley Subscription Services, Inc; Wiley
• Subjects: Genetics; Human genetics; Life Sciences; long‐read sequencing; Movement disorders; Neurobiology; Neurodegenerative diseases; Neurons and Cognition; Parkinson's disease; PRKN; PRKN; Parkinson's disease; long‐read sequencing; Structural variant; Long-read sequencing
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.29914

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.