Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing

Hagar Mor-Shaked, Emuna Paz-Ebstein, Adily Basal, Simona Ben-Haim, Hanna Grobe, Sami Heymann, Zvi Israel, Montaser Namnah, Anat Nitzan, Chaggai Rosenbluh, Ann Saada, Tomer Tzur, Shira Yanovsky-Dagan, Ronen Zaidel-Bar, Tamar Harel, David Arkadir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Biallelic pathogenic variants in PRKN (PARK2), encoding the E3 ubiquitin ligase parkin, lead to early-onset Parkinson's disease. Structural variants, including duplications or deletions, are common in PRKN due to their location within the fragile site FRA6E. These variants are readily detectable by copy number variation analysis. We studied four siblings with levodopa-responsive dystonia by exome sequencing followed by genome sequencing. Affected individuals developed juvenile levodopa-responsive dystonia with subsequent appearance of parkinsonism and motor fluctuations that improved by subthalamic stimulation. Exome sequencing and copy number variation analysis were not diagnostic, yet revealed a shared homozygous block including PRKN. Genome sequencing revealed an inversion within PRKN, with intronic breakpoints flanking exon 5. Breakpoint junction analysis implicated non-homologous end joining and possibly replicative mechanisms as the repair pathways involved. Analysis of cDNA indicated skipping of exon 5 (84 bp) that was replaced by 93 bp of retained intronic sequence, preserving the reading frame yet altering a significant number of residues. Balanced copy number inversions in PRKN are associated with a severe phenotype. Such structural variants, undetected by exome analysis and by copy number variation analysis, should be considered in the relevant clinical setting. These findings raise the possibility that PRKN structural variants are more common than currently estimated.

Original languageEnglish
Article numberfcab197
JournalBrain Communications
Issue number3
StatePublished - 2021


  • PARK2
  • PRKN
  • Parkinson's disease
  • dystonia
  • structural variants


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