Detecting somatic mosaicism: considerations and clinical implications

Abstract

Human disease is rarely a matter of all or nothing; variable expressivity is generally observed. Part of this variability is explained by somatic mosaicism, which can arise by a myriad of genetic alterations. These can take place at any stage of development, possibly leading to unusual features visible at birth, but can also occur later in life, conceivably leading to cancer. Previously, detection of somatic mosaicism was extremely challenging, as many gold standard tests lacked the necessary resolution. However, with the advances in high-throughput sequencing, mosaicism is being detected more frequently and at lower levels. This raises the issue of normal variation within each individual vs mosaicism leading to disease, and how to distinguish between the two. In this article, we will define somatic mosaicism with a brief overview of its main mechanisms in concrete clinical examples, discuss the impact of next-generation sequencing technologies in its detection, and expand on the clinical implications associated with a discovery of somatic mosaicism in the clinic.

A characterization of postzygotic mutations identified in monozygotic twins

“…The enrichment we found for mosaicism in genes associated with GTPase activity, involved in tumor growth, is in line with recent findings that larger-scale genomic mosaicisms in genes are associated with cancer (Laurie et al, 2012;Machiela et al, 2015;Vattathil & Scheet, 2016). The continuing discovery of even more cases of mosaicism provides much-needed insights into postzygotic mutational signatures (see, e.g., Ju et al 2017;Martincorena and Campbell, 2016 However, the level of mosaicism does not necessarily correlate with the severity of clinical manifestation, and mosaicism may even not have any visible effects (Cohen et al, 2015). Future research should take advantage of new technologies, for example, single cell sequencing, for high-resolution detection and localization of genetic mosaicism.…”

“…Mosaicism has been observed in several Mendelian diseases, for example, as previously mentioned in Alport Syndrome, where somatic mosaicism resulted in an unusually mild phenotype (Bruttini et al., ; Krol et al., ). However, the level of mosaicism does not necessarily correlate with the severity of clinical manifestation, and mosaicism may even not have any visible effects (Cohen et al., ). Future research should take advantage of new technologies, for example, single cell sequencing, for high‐resolution detection and localization of genetic mosaicism.…”

“…Recent research found that a fraction of presumed germline de novo mutations are actually either postzygotic or inherited as a consequence of low‐level mosaicism in one of the parents (Acuna‐Hidalgo et al., ; Rahbari et al., ), and that early postzygotic mutations could account for a substantial proportion of de novo single nucleotide variants (SNVs) in the genome of an individual (Dal et al., ). Postzygotic mosaic mutations are usually associated with cancer development (Abyzov et al., ; Biesecker & Spinner, ; Buntinx, Campbell, & van den Akker, ; Cohen, Wilson, Trinh, & Ye, ; Forsberg, Absher, & Dumanski, ; Iourov, Vorsanova, & Yurov, ; Jacobs et al., ; Laurie et al., ), but they are also an important confounder in medical genetic testing (Forsberg, Gisselsson, & Dumanski, ). A recent study suggests that somatic mosaicism in the brain might represent a potential mechanism contributing to neuronal diversity and the etiology of neuropsychiatric disorders (McConnell et al., ).…”

The SickKids Genome Clinic: developing and evaluating a pediatric model for individualized genomic medicine

“…This is due, in part, to the inability of WES to capture all exomic sequences and the difficulties encountered in using conventional short‐read NGS technologies to accurately sequence pseudogenes as well as trinucleotide repeats and other repetitive elements . Finally, clinical WES and WGS are not as sensitive as high depth gene‐specific sequencing for detecting somatic mosaicism, the cause of a small, but growing number of rare syndromes .…”

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

“…These postzygotic events (which may include mutations, large-scale rearrangements, or aneuploidies) produce a varied distribution of altered genomes throughout the individual—a phenomenon known as mosaicism (De 2011). Any cell type in the body can accumulate such mutations, including stem cells or primordial germ cell precursors, which induce permanent changes in individuals or in their offspring (Campbell et al 2015; Cohen et al 2014; Rahbari et al 2016). Recent genome-scale studies have revealed unexpected levels of mosaicism in seemingly normal tissues (Campbell et al 2015; Erickson 2010; Rahbari et al 2016), and we may still be vastly underestimating the prevalence and health burden of low-level mosaicism (Campbell et al 2014; Spinner and Conlin 2014).…”