Somatic copy number variants in neuropsychiatric disorders

Abstract

Copy number variants (CNVs) have been implicated in neuropsychiatric disorders, with rare-inherited and de novo CNVs (dnCNVs) having large effects on disease liability. Recent studies started exploring a class of dnCNVs that occur post-zygotically, and are therefore present in some but not all cells of the body. Analogous to conditional mutations in animal models, the presence of risk mutations in a fraction of cells has the potential to enlighten how damaging mutations affect cell-type/cell-circuit specific pathologies leading to neuropsychiatric manifestations. Although mosaic CNVs appear to contribute to a modest fraction of risk (0.3-0.5%), expanding our insights about them with more sensitive experimental and statistical methods, has the potential to help clarify mechanisms of neuropsychiatric disease.

Figure 1.

Inherited, de novo, and somatic CNVs affect a different proportion of cells and tissues. (A) Inherited CNVs are present in all cells of the parent and are transmitted to the offspring during fertilization, causing all the child’s cells to carry the variant. (B) De novo CNVs occurring in the parental germ cells can pass the variant to the offspring during fertilization, resulting in all child’s cells carrying the variant. (C) Somatic CNVs can occur before gastrulation and organ cell commitment resulting in these variants to be present in a fraction of cells in several tissues such as brain and blood. (D) If somatic CNVs occur after gastrulation they can be organ specific, with variants arising during cortical neurogenesis present in the brain - later occurring variants can be more focal.

Figure 2.

Approaches to study somatic CNVs in neuropsychiatric disorders. The most used tissues for the study of somatic CNVs are blood and post-mortem brain tissue. These approaches have technical considerations to have favored/limited their use to answer specific question. Most of the current somatic CNV burden estimates for neuropsychiatric disorders come from blood studies, however these are likely to be underestimates as there are limited to early events. While the study of post-mortem brain tissue has provided insights into somatic CNV rates in the non-diseased brain, the small sample sizes of neuropsychiatric studies limits the generalizability of their findings in a neuropsychiatric disease context.