Objective: In this study, we aimed to investigate the frequency and phenotypical features in a subset of early-onset Parkinson’s disease (EO-PD) (age-at-onset ≤45 years) patients due to genomic rearrangements in PARK2, PINK1 and DJ-1.

Background: EO-PD, constituting around 10% of all PD cases, is frequently associated with autosomal recessive (AR) mutations of PARK2 (PARKN), PINK1 and DJ-1 genes. Among all different types of mutations, genomic rearrangements are common at varying degrees depending on the ethnicity of the population.

Methods: Thirty-five unrelated Turkish EOPD patients, whose clinical features are suggestive of AR-PD were recruited from our outpatient clinic. After structured clinical evaluation, the patients were screened for genomic rearrangements by using the multiplex ligation-dependent probe amplification (MLPA) method with SALSA P051 kit, before sequence analysis. The kit consists of probes for all exons of α-synuclein, PRKN, and PINK1, and specific exons of DJ-1; LRRK2; UCH-L1; ATP13A2; LPA; TNFRSF9; CAV2; CAV1 and GCH1.

Results: We identified exonic rearrangements in 47% of 34 Turkish patients. We have identified 11 patients (32%) with homozygous whole exonic deletions in exons 2, 3, 4, and 5 of PRKN gene, 4 patients (12%) with heterozygous whole exonic deletions in PRKN gene in exons 2, 3, 4, and 5. Exon 4 and 5 were found to be the most frequently deleted sites in PRKN gene. Clinically, the mean age at onset was found to be younger in the homozygous PRKN deletion group compared to heterozygous group (26±9 vs. 35±8), also with better UPDRS scores (10.5 vs 16.25) despite similar disease duration. Among motor and non-motor presenting features, sleep benefit (80%) and gait abnormality (60%) were the most common ones. Additionally, one patient was found to have homozygous whole exonic deletions in DJ-1 (in exons 1, 3, and 5). No genomic rearrangements were found in PINK-1 gene. Further genotyping continues for possible point mutations.

Conclusions: PRKN mutations are the most common cause of early onset AR-PD in Turkey. Genomic rearrangements of PRKN was found in high proportion in our study group. Therefore, we suggest that MLPA test provides a high yield for positive diagnosis of PRKN mutations as a first step of genotyping in possible AR-PD cases with early onset. In addition, we have identified DJ-1 mutation in one patient, being the first genomic rearrangement reported from Turkey.

References: Acknowledgements: This part of study is supported by a collaborative project ‘Genotyping and Cellular Phenotyping of Subjects with Familial Parkinson’s Disease Mutation’ with Hacettepe University and Luxembourg Centre for Systems Biomedicine.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/how-common-are-the-genomic-rearrangements-among-possibly-autosomal-recessive-pd-cases-in-turkey/