Mosaic structural variation in children with developmental disorders

Abstract

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

“…bristol.ac.uk/alspac/) (N 5 3290 children) and the Twins Early Development Studies (http://www.teds.ac.uk/) (N 5 1804 children). 16 …”

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

“…One sample, with three mosaic abnormalities detected on a single chromosome, which had also been detected during an earlier analysis (King et al 2015), provided a valuable opportunity to use whole-genome sequencing data to clarify rearrangement architecture and to demonstrate MrMosaic performance on wholegenome sequence data. After the whole-genome sequencing data were generated and analyzed, MrMosaic easily detected these multi-megabase mosaic events, found with Mscores of 36, 117, and 32.…”

“…To improve our understanding of the accuracy of this sequencing-based method, we compared the results of the above analysis with the results of a prior experiment (King et al 2015), which had analyzed high-resolution SNP data of 1303 Deciphering Developmental Disorders (DDD) samples, among which 1226 (of the 1303) had both exome and SNP data available. Among these 1226 for which the exome data could be compared with the gold-standard SNP data, detection using MrMosaic identified eight events, whereas detection using SNP microarray data of probands identified 10 events.…”

“…Of the nine children presented here, four (Decipher IDs: 261373, 259003, 260462, and 257978) had been discovered and examined for pathogenicity during an earlier study (see Table 2; Supplemental Note S1; King et al 2015). The mosaic events identified in seven of nine children were considered definitely pathogenic because they were multi-megabase CNVs that overlap known genomic-disorder regions (Supplemental Note S1).…”

“…Low-clonality mosaicism is difficult to observe in karyotyping, as inspection of at least 20 cells is required to exclude 14% mosaicism with 95% confidence (Hook 1977), and it is also difficult to observe in microarray analysis, because the detection sensitivity of mosaic duplications by SNP microarray with about 1 million probes for events of at least 2 Mb in size is limited to events of ∼10% clonality (Gonzá-lez et al 2011;Jacobs et al 2012;Laurie et al 2012;Machiela et al 2015). 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.…”