Low-Level Chromosomal Mosaicism in Neurodevelopmental Disorders

Abstract

Chromosomal mosaicism, which represents a diagnostic challenge for detection and interpretation, has been described in several genetic conditions. It can contribute to a large phenotypic variation in diseases. At analysis of a well-characterized cohort of 714 patients with neurodevelopmental disorders (NDDs) of unknown etiology using a high-resolution chromosomal microarray platform, we found 2 cases (0.28%) of low-level mosaicism and defined a previously detected extra chromosome in a third patient. Two of the cases were mosaics for segmental imbalances (a partial trisomy 3q26.1q27.3 and a partial monosomy 18q21.2qter with 14.6 and 20% mosaic ratios in lymphocytes, respectively), and 1 was a mosaic for an entire chromosome (trisomy 14, mosaic ratio 20%). Our diagnostic yield is in line with the ratios previously published in patients with intellectual disability. Notably, the partial trisomy 3q26.1q27.3 case is an example of a rare and unusual class of a rearranged neocentric ring chromosome, which can neither be categorized in class I, nor in class II of such rearrangements. Our cases further elucidate the phenotypes related to the aberrations of the specific chromosome segments observed and underline the important role of low-level mosaics in the pathogenesis of NDDs of unknown etiology even in the absence of clinical signs of mosaicism.

Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions

“…In the case of patients with high proportions of cells with NF1 microdeletions in their blood, normal cells not harbouring the deletion and present at proportions lower than 10-20% are not detected by MLPA. Similar detection limits are associated with other methods such as microarray analysis and Sanger sequencing (Tsiatis et al 2010;Davidson et al 2012;Oneda et al 2017;Kumar et al 2018). However, next generation sequencing methods including ultra-deep amplicon sequencing with high coverage of the target regions (> 1000 sequence reads), have been shown to detect lowgrade somatic mosaicism down to a level of only a few percent (reviewed by Cohen et al 2015; and reviewed by Gajecka, 2016;Contini et al 2015;Quin et al 2016;Bernkopf et al 2017;Chang et al 2017;Morimoto et al 2017).…”

International consensus recommendations on the diagnostic work-up for malformations of cortical development

“…Single nucleotide polymorphism arrays have the advantage of detecting regions of homozygosity, thereby facilitating diagnostics in consanguineous families. Mosaic CNVs showing as little as 15-20% chromosomal mosaicism were successfully detected in patients with neurode velopmental disorders 153 . We anticipate that CMA will become redundant in the future as NGS costs further decrease and algorithms for CNV analysis from NGS data become more robust.…”

Epilepsy panel testing criteria: A clinical assessment

“…Typically, these rearrangements do not cause disease in the affected individual unless a particular gene is disrupted as a result. Additionally, CMA cannot detect the presence of low-level mosaicism (i.e., mosaicism below 20-25%) in body tissues, which has been shown to contribute to patient phenotypes in several cases involving intellectual and developmental disability, atresia of the auditory canal, and post-axial polydactyly (Oneda et al, 2017). Finally, unlike NGS technology, CMA cannot detect single nucleotide changes, or point mutations, in the DNA sequence (Levy & Wapner, 2018).…”