Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10 362 consecutive cases

Abstract

Somatic chromosomal mosaicism arising from post-zygotic errors is known to cause several well-defined genetic syndromes as well as contribute to phenotypic variation in diseases. However, somatic mosaicism is often under-diagnosed due to challenges in detection. We evaluated 10 362 patients with a custom-designed, exon-targeted whole-genome oligonucleotide array and detected somatic mosaicism in a total of 57 cases (0.55%). The mosaicism was characterized and confirmed by fluorescence in situ hybridization (FISH) and/or chromosome analysis. Different categories of abnormal cell lines were detected: (1) aneuploidy, including sex chromosome abnormalities and isochromosomes (22 cases), (2) ring or marker chromosomes (12 cases), (3) single deletion/duplication copy number variations (CNVs) (11 cases), (4) multiple deletion/duplication CNVs (5 cases), (5) exonic CNVs (4 cases), and (6) unbalanced translocations (3 cases). Levels of mosaicism calculated based on the array data were in good concordance with those observed by FISH (10–93%). Of the 14 cases evaluated concurrently by chromosome analysis, mosaicism was detected solely by the array in 4 cases (29%). In summary, our exon-targeted array further expands the diagnostic capability of high-resolution array comparative genomic hybridization in detecting mosaicism for cytogenetic abnormalities as well as small CNVs in disease-causing genes.

Detection of structural mosaicism from targeted and whole-genome sequencing data

“…One likely explanation for the discrepancy in these frequencies is ascertainment bias, as some classes of structural mosaicism (e.g., mosaic trisomies) are likely to have been diagnosed by prior diagnostic testing (e.g., karyotype or microarray) and not enrolled into the DDD study. Another component of this discordance may be due to decreased sensitivity, as mosaicism smaller than 2 Mb is challenging to detect by exome, and these small events account for ∼25% (9/36) of mosaic copy number events described previously (Pham et al 2014). Given the low number of mosaic events in our cohort, due to the low mosaicism rate and tissue specificity, and the lack of publicly available largescale developmental disorder data sets, this study only provides a limited estimate of the real-life performance of MrMosaic on nonsimulated data sets.…”

“…The median average clonality in recent SNP-based studies of DD for mosaic aneuploidy was 40% (Conlin et al 2010), and for mosaic structural variation (2 Mb and greater), it was 44% (King et al 2015). With regard to frequency of mosaicism among children investigated with clinical diagnostic testing, the proportion of autosomal mosaic copy-neutral events was 0.24% (12 in 5000) (Bruno et al 2011), whereas the proportion of autosomal mosaic copy-number events was 0.35% (36 in 10,362) (Pham et al 2014); summing both copy-neutral and copy-number proportions yields a combined proportion of 0.59% of cases with mosaic structural variation.…”

Recent advances in the study of somatic mosaicism and diseases other than cancer

“…One large study of pathogenic CNVs in children with developmental delay or otherwise unexplained congenital abnormalities found 10% of them to be somatically mosaic (using SNP arrays) [29 ]. Comparative genomic hybridization (CGH) in non-neurological patients also finds high yields of somatic mosaicism [30,31]. This is probably on the order of the percentage of de novo point mutations and insertions/ deletions (indels), which are due to somatic mosaicism.…”

Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays☆

“…These array-based methods are now being used in the clinic to identify the sources of idiopathic diseases [120][121][122][123][124] and are the main technologies used to identify CNVs. However, very little work has been carried out to explore the effect of mutagens on CNV formation.…”