Microarray‐based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics

Abstract

Somatic chromosomal mosaicism is a well-established cause for birth defects, mental retardation, and, in some instances, specific genetic syndromes. We have developed a clinically validated, targeted BAC clone array as a platform for comparative genomic hybridization (aCGH) to enable detection of a wide range of pathologic copy number changes in DNA. It is designed to provide high sensitivity to detect well-characterized submicroscopic micro-deletion and duplication disorders while at the same time minimizing detection of variation of uncertain clinical significance. In the course of studying 2,585 samples submitted to our clinical laboratory, chromosomal mosaicism was detected in 12 patient samples; 10 of these cases were reported to have had a normal blood chromosome analysis. This enhanced ability of aCGH to detect mosaicism missed by routine chromosome analysis may be due to some combination of testing multiple cell lineages and/or failure of cytogenetically abnormal T lymphocytes to respond to mitogens. This suggests that aCGH may detect somatic chromosomal mosaicism that would be missed by conventional cytogenetics.

Comparison of chromosome analysis and chromosomal microarray analysis: what is the value of chromosome analysis in today’s genomic array era?

“…Two of these cases were reported previously as case 8 (mosaic trisomy 14) and 9 (mosaic trisomy 22). 6 Mosaicism was suspected by the CMA plot, with log ratios ranging between 0.04 and 0.22 and confirmed by FISH analysis on a blood smear or phytohemagglutinin-stimulated T cells showing mosaicism levels ranging from 6.5% to 29%. The log ratios correlate with the percentage of trisomic cells revealed by FISH, except for case 9, 6 who had a lower level of trisomic cells by FISH than expected by the log ratio, probably because the FISH analysis was performed on a 2-week-old uncultured blood sample.…”

“…Studies have demonstrated that CMA may be more sensitive when abnormal cells fail to respond to mitogens and/or abnormalities are rare or absent in T cells, such as in PallisterKillian syndrome. 5,6 Five cases of mosaic trisomy, involving chromosomes 8, 9, 14, and 22, were detected only by CMA.…”

“…6,13,14 Other array platforms, such as single-nucleotide polymorphism arrays may be better capable of detecting mosaicism by the information obtained from the B-allele frequencies. 15,16 Chromosome analysis can detect low-level mosaicism through the individual examination of large numbers of cells.…”

Genome-wide arrays: Quality criteria and platforms to be used in routine diagnostics

“…There may be occasions when the result from direct material differs from that from cell culture. There are several reports that array-CGH can detect mosaic aberrations that are not observed on cultured material [Ballif et al, 2006;Cheung et al, 2007;Gardner and Sutherland, 2004]. However, when a discordant result is found, confirmation of the abnormality is advisable, preferably by fluorescence in situ hybridization (FISH) analysis on uncultured material if possible.…”

Uso da FISH em mucosa oral para investigação de mosaicismo com linhagem 45,X: estudo com homens saudáveis e pacientes com distúrbios da diferenciação do sexo

“…Quando esses eventos ocorrem na mitose podem ocasionar mosaicismo, ou seja, presença de duas ou mais linhagens cromossomi camente distintas (1). Estudos no período inicial do de senvolvimento embrionário após fertilização in vitro su gerem que o mosaicismo ocorre em 50% dos embriões até o estágio de oito células e 75% dos blastocistos (2).…”