Mosaic structural variation in children with developmental disorders.

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.

Microdeletion 1p35.2: a recognizable facial phenotype with developmental delay.

We describe two patients with microdeletion 1p35.2, intrauterine growth retardation, small stature, hypermetropia, hearing impairment and developmental delay. Both patients have long, myopathic facies, with fine eyebrows, small mouths and micrognathia. We postulate a role for the histone deacetylase HDAC1 in the facial phenotype and suggest that deletion of KPNA6 may prevent transmission of the 1p35.2 deletion from affected girls to any offspring through impaired zygotic genome activation.

A case of mosaic trisomy 19q12-q13.2 with high BMI, macrocephaly, and speech delay: does USF2 determine size in the 19q phenotypes?

Hall et al. (2010) describe a boy with mosaic trisomy of the proximal part of 19q, with obesity, macrocephaly and global developmental delay. The patient is interesting with regard to his cytogenetic abnormality, which is smaller than those previously reported, and does not include the candidate obesity and insulin-resistance genes identified by other authors (Zung et al., 2007; Davidsson et al., 2010) as possible causes of the overweight/obesity seen in four of five previously documented patients. This suggests that a novel obesity locus may reside in the duplicated region 19q13.11­q13.2. We present a phenotypically similar boy with intrachromosomal insertion of material derived from proximal 19q into proximal 19p, causing mosaic trisomy 19q12­q13.2, and consider the role of USF2, a master transcriptional regulator of metabolic genes, in 19q phenotypes.