Somatic Mutations Detected in Parkinson Disease Could Affect Genes With a Role in Synaptic and Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. However, to date, no study has shown their relation to Parkinson disease's phenotype. To explore the relevance of embryonic somatic mutations in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and a careful filtering strategy (COSMOS). We validated 27 of them with amplicon-based ultra-deep sequencing, with a 70% validation rate for the highest-confidence variants. The identified sSNVs are in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. Most of the sSNVs were only called in blood but were also found in the brain tissues with ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. This work was supported by the grants from the Spanish MINECO and MICIN (SAF2016-76340R and PID2019-106764RB-C21, Excellence Unit María de Maeztu/Institute of Neurosciences), CIBERNED (ISCIII), and by the “Fundación Reina Sofía” (Exome Project) awarded to ES, by RTI 2018-096824-B-C22 grant from Agencia estatal de Investigación- Spanish Ministry of Science, Innovation and Universities co-financed by FEDER, and by Direcció General de Recerca, Generalitat de Catalunya (2017SGR-702) to FC, MS-M is supported by the Ministerio de Economía y Competitividad, Spain (Maria de Maetzu grant MDM-2014-0370-16-3). PE-C was supported by a Formació de Personal Investigador fellowship from Generalitat de Catalunya (FI_B00122). RR is funded by Cancer Research UK (C66259/A27114).