An Organismal CNV Mutator Phenotype Restricted to Early Human Development

Abstract

Summary De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient peri-zygotic period. We propose that a defect in the CNV formation process is responsible for the ‘CNV-mutator state’, and that this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution and cancer biology.

Genomic disorders 20 years on—mechanisms for clinical manifestations

“…The active CNV mutation shower, which also included de novo point mutations flanking the rearrangement junctions consistent with replicative repair, appeared to be restricted to a transient perizygotic period. WES performed on selected subjects did not identify specific gene variants that could potentially drive the MdnCNV phenotype, suggesting that the causal mutation resides in an unknown disease gene, noncoding region of a critical gene, or that the driver mutation is lost or suppressed after triggering a CNV mutator phenotype …”

“…As mentioned above, a multiple de novo CNV phenomenon was recently described, in which individuals with genomic disorders carry multiple constitutional CNVs which seem to arise during a specific timeframe during embryonic development. The formation of multiple de novo mutations has no known genetic or environmental trigger as of yet . This “mutation shower” differs from multilocus variation or a mutational burden, wherein both inherited and de novo CNVs and SNVs aggregate within an individual genome and modify phenotypic expression (Figure C), for instance by biological pathway interactions as exemplified by the ciliopathies and the neuropathies …”

“…WES performed on selected subjects did not identify specific gene variants that could potentially drive the MdnCNV phenotype, suggesting that the causal mutation resides in an unknown disease gene, noncoding region of a critical gene, or that the driver mutation is lost or suppressed after triggering a CNV mutator phenotype. 50…”

“…The formation of multiple de novo mutations has no known genetic or environmental trigger as of yet. 50 This "mutation shower" differs from multilocus variation or a mutational burden, wherein both inherited and de novo CNVs and SNVs aggregate within an individual genome and modify phenotypic expression 103 (Figure 2C), for instance by biological pathway interactions as exemplified by the ciliopathies [112][113][114] and the neuropathies. 115…”

Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes

“…Data were analyzed using the novoBreak assembly algorithm to detect breakpoint junctions (Figure 1E) (Chong et al, 2017; Liu et al, 2017). In total, 6 junctions were identified through a combination of aCGH and WGS analyses; of those junctions, 5 were confirmed through traditional Sanger-sequencing (Supp.…”