The utility of chromosomal microarray analysis in developmental and behavioral pediatrics

Abstract

Chromosomal microarray analysis (CMA) has emerged as a powerful new tool to identify genomic abnormalities associated with a wide range of developmental disabilities including congenital malformations, cognitive impairment, and behavioral abnormalities. CMA includes array comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, both of which are useful for detection of genomic copy number variants (CNV) such as microdeletions and microduplications. The frequency of disease-causing CNVs is highest (20%-25%) in children with moderate to severe intellectual disability accompanied by malformations or dysmorphic features. Disease-causing CNVs are found in 5%-10% of cases of autism, being more frequent in severe phenotypes. CMA has replaced Giemsa-banded karyotype as the first-tier test for genetic evaluation of children with developmental and behavioral disabilities.

Figure 1

Comparison of metaphase and interphase FISH. Panel a shows metaphase FISH for a deletion detected by the presence of a red signal on the normal chromosome and not the deleted chromosome. Panel b shows interphase FISH with duplication on the chromosome with two red signals and one red signal on the normal chromosome. (See the online version of this article for Figure 1 in color.) Provided by Ankita Patel and Sau Wai Cheung; used by permission of Baylor College of Medicine.

Figure 2

Array CGH showing a deletion on chromosome 17 encompassing the neurofibromatosis 1 (NF1) gene and 11 other genes. The study was performed using the Agilent platform. Each dot in the “All chromosomes” view represents a bin of oligonucleotides, while each dot in the other views represents a single oligonucleotide. Black ovals indicate the deleted region. Red ovals indicate the nondeleted oligonucleotides nearest the deletion. The black square at the Y chromosome indicates a benign copy number variation. (See the online version of this article for Figure 2 in color.) Provided by Ankita Patel and Sau Wai Cheung; used by permission of Baylor College of Medicine.

Figure 3

Single nucleotide polymorphism arrays showing a deletion of chromosome 1 (top) and a duplication of chromosome 22 (bottom) using the illumina 610 quad platform. For the deletion in the upper panel, the absence of AB genotype in the B allele data is shown by the upper black oval. The decreased copy number is shown by the lower black oval. For the duplication in the lower panel, the region with AAB and ABB genotypes is shown by the upper black oval and the gain in copy number by the lower black oval. Provided by Joanna Wiszniewska; used by permission of Baylor College of Medicine.

Figure 4

Single nucleotide polymorphism (SNP) array for a case of Prader-Willi syndrome caused by maternal uniparental disomy for chromosome 15. Analysis was performed on the illumina SNP array platform. The B allele ratio is shown above with AA, AB, and BB genotypes indicated. The copy number is shown below and is normal. There are two regions of isodisomy of 39.5 and 6.4 megabases (Mb), and the intervening segment shows heterodisomy. Provided by Joanna Wiszniewska; used by permission of Baylor College of Medicine.