Objective: (i) To identify complex variants usually not visible by short-read whole exome sequencing in known genes of Parkinson’s disease (PD) such as structural variants and short tandem repeats and (ii) to discover new PD genes.

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer’s disease, affecting more than 1% among people older than 60 years old. Although the etiology is mostly unknown, an early onset, a familial form and an atypical presentation might evoke a monogenic etiology. To date, more than a dozen causative genes have been identified and validated, however they only explain a small fraction of early onset and familial PD (~ 5-10%). Therefore, more genes are to discover.

Long-read whole genome sequencing (LR-WGS) emerged recently. It drastically overcomes the limited ability of short-read whole exome sequencing to identify structural variants and short tandem repeats. Interestingly, pathogenic repeat expansions were identified in early onset and familial PD using LR-WGS technology in genes such as RFC1 or NOTCH2NLC, supporting the utility of long-read in the context of PD.

Method: We performed LR-WGS in a total of 106 individuals (100 PD patients and 6 relatives) with early-onset and/or a positive family history, all of them left genetically undiagnosed after whole exome sequencing.

Results: 97 were familial cases from 40 families and nine were isolated cases. Among these 40 families, 31 were compatible with autosomal dominant and nine with autosomal recessive inheritance mode. Male/Female sex ratio was 1.7 and average age at onset 46.8 years old (range 10 to 79 years old). Using this approach, we identified (i) complex structural variants in known PD-genes unidentifiable by classic genetic testing methods (PRKN), (ii) pathogenic repeat expansions in genes involved in neurological disorders with Parkinsonism (FMR1) and (iii) potential new candidate genes for PD (PDE10A).

Conclusion: The application of new sequencing technologies like LR-WGS appears to be an efficient strategy to decipher the genetic architecture of unsolved complex neurological disorders such as PD and to further understand the mechanisms of the disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/utility-of-using-long-read-whole-genome-sequencing-to-solve-exome-negative-early-onset-and-familial-parkinsons-disease-a-series-of-106-individuals/