TY - JOUR
T1 - Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing
AU - Mor-Shaked, Hagar
AU - Paz-Ebstein, Emuna
AU - Basal, Adily
AU - Ben-Haim, Simona
AU - Grobe, Hanna
AU - Heymann, Sami
AU - Israel, Zvi
AU - Namnah, Montaser
AU - Nitzan, Anat
AU - Rosenbluh, Chaggai
AU - Saada, Ann
AU - Tzur, Tomer
AU - Yanovsky-Dagan, Shira
AU - Zaidel-Bar, Ronen
AU - Harel, Tamar
AU - Arkadir, David
N1 - Publisher Copyright: © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - PARK2
KW - PRKN
KW - Parkinson's disease
KW - dystonia
KW - structural variants
UR - http://www.scopus.com/inward/record.url?scp=85133870706&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/braincomms/fcab197
DO - https://doi.org/10.1093/braincomms/fcab197
M3 - مقالة
C2 - 34514401
SN - 2632-1297
VL - 3
JO - Brain Communications
JF - Brain Communications
IS - 3
M1 - fcab197
ER -