Long-read sequencing to solve exome negative Parkinson's disease

Abstract

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. 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 be discovered. Recently, pathogenic repeat expansions were identified in early onset and familial PD using long-read whole-genome sequencing (LR-WGS) technology in genes such as RFC1 or NOTCH2NLC, supporting the utility of long-read sequencing in the context of PD. We performed nanopore sequencing on a total of 106 individuals (100 PD patients and six relatives) with early-onset and/or a positive family history, all of them left genetically undiagnosed after whole-exome sequencing. Ninety-seven 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. The male/female sex ratio was 1.7 and average age at onset 46.8 years old (range 10 to 79 years). Using this approach, we identified (i) complex structural variants in known PD-genes (PRKN), (ii) pathogenic repeat expansions in genes involved in neurological disorders with Parkinsonism (SCA8), and (iii) potential new candidate genes for PD (PDE10A). Thus, long-read whole-genome sequencing appears as an efficient future strategy to decipher the genetic architecture of unsolved complex neurological disorders.

Biography

Guillaume is an MD in medical genetics and PhD student at the Paris Brain Institute, working mostly in neurodegenerative disorders. Using nanopore sequencing, he has sequenced more than a hundred early-onset and familial Parkinson's disease patients in order to identify new PD genes during his master's degree at the Center for Alzheimer's and related dementia at NIH in 2023. Guillaume is also interested in medical and research ethics having obtained a related master's degree at the University of Paris-Saclay in 2022.