Multiple system atrophy is associated with brain somatic mutations in clonal hematopoiesis genes

ABSTRACT Background Multiple system atrophy (MSA) is a sporadic disorder characterized by alpha-synuclein inclusions. Somatic mutations may contribute to neurodegeneration, with somatic copy number variants in SNCA (alpha-synuclein) reported in MSA, and somatic mutations in cancer driver genes in Alzheimer’s disease. Objectives To investigate whether small somatic mutations (single nucleotide variants [SNVs] and indels) in SNCA , KCTD7 , and 10 cancer driver genes, including seven involved in clonal hematopoiesis (CH), are present in MSA brain. Methods We applied duplex sequencing with unique molecular identifiers to DNA from cerebellum, cingulate cortex, and putamen of 20 MSA cases (10 olivopontocerebellar atrophy [OPCA], 10 striatonigral degeneration [SND]) and nine controls. Results We detected 34 somatic mutations, including 14 in CH genes. CH gene mutations were elevated in MSA compared to controls, reaching significance in the cortex (p=0.033), most prominently in SND (p=0.011), which also showed putaminal enrichment (p=0.034). Multi-regional CH mutations were only detected in MSA (six cases, all brain regions in three). There were 10 coding CH mutations, eight of which were in MSA, including six multi-regional. MSA CH mutations included events with oncogenic potential. Both coding CH mutations in controls were restricted to the cerebellum. No coding variants were detected in SNCA , and neither SNCA nor KCTD7 showed excess somatic mutations. Conclusions Somatic CH mutations are enriched in MSA brain. Their multi-regional presence and predicted oncogenic potential suggest a functionally relevant proliferative process extending beyond peripheral hematopoiesis. Somatic SNVs and indels in SNCA and KCTD7 do not appear to be common MSA drivers.