Objective: To assess the diagnostic yield of clinical exome sequencing (CES) in individuals with Parkinson’s disease (PD) seen in a specialized movement disorder clinic.

Background: PD is genetically heterogeneous disorder. Therefore, a large number of genes have to be screened in order to identify a causal variant in a patient. CES offers the possibility to analyze the majority of genes in the human genome in a single test. It detects single nucleotide variants and small insertions and deletions with high quality and, in some cases, allows the detection of copy number variants such as deletions of one or more exons. We wanted to test the application of CES in the diagnosis of PD in a randomly selected German PD group.

Methods: Currently, a total of 11 individuals with PD have been recruited in a movement disorder clinic in Kassel, Germany. Selection for exome sequencing was based on age of onset of the disease (< 40 years) in order to enrich for hereditary forms of disease. Exomes were captured and indexed with SureSelect XT Human All Exon 50Mb kit version 5 (Agilent). Sequencing was performed as 100-bp paired-end reads on a HiSeq2500 system (Illumina) and raw data processed with Illumina Real Time Analysis. Reads were aligned against the human assembly hg19 using BWA. Variants were called using SAMTools and Pindel and annotated with custom Perl scripts.

Results: Initial analysis focused on known and validated genes causing monogenic PD identified the genetic cause in 2 out of 11 patients, which carried known pathogenic variants in LRRK2 and PINK1. In addition, we found heterozygous carriers of rare (allele frequency < 1% in European (non-Finnish) ExAC browser dataset) variants in PARK2 (3/11) and in GBA (2/11). No rare variants were detected in VPS35, EIF4G1, SNCA, and DJ-1. For all these genes, the coverage of coding regions was high.

Conclusions: For 1/6th of patients, CES identified the genetic cause of disease. The identification of heterozygous carriers of variants in PARK2 and GBA supports the notion that they are risk factors for developing parkinsonism. For the majority of patients, no causal variant was identified despite the young-onset population, highlighting the current challenges of variant interpretation in CES. However, CES data can be reanalyzed at any time incorporating new data, with the prospect of diagnostic findings in currently unsolved cases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-exome-sequencing-diagnostic-yield-in-a-sample-of-german-patients-with-parkinsons-disease/