To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10 per base pair per individual. These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.
The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances. Neuropathological assessment revealed widespread β-amyloid (Thal phase 5) and tau (Braak stage 6) pathology. Abundant deposition of diffuse and cored plaques was distributed in cortical and subcortical areas, as well as in the cerebellum, while cotton wool plaques were observed mainly in the occipital cortex. Cerebral amyloid angiopathy was present throughout the brain. In the neocortex, tau pathology, especially neuropil threads, was more abundant in the frontal and occipital cortex and in the hippocampus. Proteomic analyses revealed that the pattern of sarkosyl-insoluble tau was similar to the one seen in sporadic AD. No α-synuclein or TDP-43 pathology was found either in cortical nor in subcortical areas. Here, we present the first comprehensive neuropathological and biochemical study of early onset FAD with a missense mutation Thr116Asn in the presenilin 1 gene. In contrast to other PS1-linked AD patients, the present subject developed cotton wool plaques which were not associated with spastic paraparesis.