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.

Figure 1.

Overview. A MAD-based workflow was used to detect mosaicism. This workflow identified an enrichment of mosaicism in cases compared with controls, and triPOD detected two additional mosaic events not detected by MAD. Clinical assessment was performed on all 12 probands of the DDD study with mosaicism.

Figure 2.

The (A) sample number and (B) ages corresponding to the analysed studies.

Figure 3.

The frequency of mosaicism detected in the parents of the trio cohorts was within the confidence intervals of the frequency detected for samples of this age range.

Figure 4.

(A) The percentage of samples with mosaic events in the case and control cohorts. (B) A depiction of each mosaic event, where the line segments represent the ideal location of mosaicism for gains (blue), LOH (orange) and losses (red).

Figure 5.

All Proband Detections: The detections made by (A) MAD & triPOD, (B) by MAD alone and (C) by triPOD alone.