AB024. Chromosome microarray analysis (CMA) for the diagnosis of children with developmental delay and multiple congenital anomalies in Singapore

Abstract: Chromosome microarray analysis (CMA) is a sensitive method to identify submicroscopic changes too small to be detected by conventional karyotyping. Due to its high-sensitivity in identifying regions with structural variation and hence the genes involved, it is recommended to be the first-tier genetic test for children with intellectual disabilities, development delay or multiple congenital anomalies, and is routinely available in USA and many countries in Europe. Our lab has started offering this as a clinical test based on the research experience on screening >400 children with developmental delay and multiple congenital anomalies since February 2014. To date, 271 patients have been screened using the Agilent 4×180K CGH + SNP array. Copy number variants (CNVs) ranging in size from 10 kb to 154 Mb were found in 109 patients (40%). Pathogenic and likely pathogenic CNVs were found in 55 (20%). These included 45 with deletions, 8 with duplications and 2 patients with both deletion and duplication. Recurrent microdeletion and microduplication syndromes including the Angelman/Prader-Willi syndrome [5], 1p36 microdeletion [3], Williams syndrome [2], 22q11.2 distal deletion syndrome [2], 16p13.3 microdeletion syndrome [2], Cat Eye syndrome, Cri du Chat syndrome, Miller Decker syndrome, 3q29 microdeletion, 15q24 microdeletion, and 1q43q44 syndrome were among the variants detected in our patients. CNVs of uncertain clinical significance were detected in 54 (20%) individuals: 32 were duplications, 18 were deletions and one with both deletion and duplication. However, due to the high cost of the test, parental testing was not performed and hence, significance of these variants could not be established conclusively. In conclusion, CMA is a powerful tool in identifying pathogenic chromosomal copy number alternations. However, due to the high cost of the test, parental testing for the cases where variants of uncertain significant are found is often not possible. CMA is useful in identifying pathogenic structural rearrangement. More data are necessary to be collected to enhance interpretation of the results.

Keywords: Chromosome microarray; developmental delay; multiple congenital anomalies; microdeletion; microduplication