The role of de novo mutations in adult-onset neurodegenerative disorders

Abstract

The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient-parent trios allows a hypothesis-free study of the role of de novo mutations in AOND and the discovery of novel disease genes. Another hypothesis that may explain a proportion of sporadic AOND cases is the occurrence of a de novo mutation after the fertilization of the oocyte (post-zygotic mutation) or even as a late-somatic mutation, restricted to the brain. Such somatic mutation hypothesis, that can be tested with the use of novel sequencing technologies, is fully compatible with the seeding and spreading mechanisms of the pathological proteins identified in most of these disorders. We review here the current knowledge and future perspectives on de novo mutations in known and novel candidate genes identified in the most common AONDs such as Alzheimer's disease, Parkinson's disease, the frontotemporal lobar degeneration spectrum and Prion disorders. Also, we review the first lessons learned from recent genomic studies of control and diseased brains and the challenges which remain to be addressed.

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…These mutations could impair neuronal health and function in largely undefined ways. Interestingly, somatic mutations or variants in brain neurons with low allele frequency has been associated with aging and neurodegenerative diseases [125][126][127]. This somatic mosaicism has, in particular, been demonstrated in AD brains.…”

Investigation of Somatic Mutations in Human Brains Targeting Genes Associated With Parkinson's Disease

“…In this study, we expanded our search to other PD-genes. We excluded as many cases as possible with long disease duration and late-onset, as somatic variants playing a role in disease are hypothesized to be less likely to occur in these cases (16,17). We included a patient carrying a LRRK2 G2019S mutation, who had a phenotypically discordant monozygotic twin and where somatic variation could have played a role in penetrance (11).…”

Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia

“…Indeed, pre-existing retrotransposons may act as "lightning rods" for novel insertions, which may modulate gene expression (49). Specifically, de novo PZMs have been reported in a number of neurodegenerative (57,58) as well as neurodevelopmental diseases (59)(60)(61). Of special interest to this discussion is the high frequency of de novo mutations reported in patients for neurodevelopmental disorders such as autism (62) and schizophrenia (63)(64)(65)(66).…”