Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing

Abstract

In clinical diagnostics, both array comparative genomic hybridization (array CGH) and single nucleotide polymorphism (SNP) genotyping have proven to be powerful genomic technologies utilized for the evaluation of developmental delay, multiple congenital anomalies, and neuropsychiatric disorders. Differences in the ability to resolve genomic changes between these arrays may constitute an implementation challenge for clinicians: which platform (SNP vs array CGH) might best detect the underlying genetic cause for the disease in the patient? While only SNP arrays enable the detection of copy number neutral regions of absence of heterozygosity (AOH), they have limited ability to detect single-exon copy number variants (CNVs) due to the distribution of SNPs across the genome. To provide comprehensive clinical testing for both CNVs and copy-neutral AOH, we enhanced our custom-designed high-resolution oligonucleotide array that has exon-targeted coverage of 1860 genes with 60 000 SNP probes, referred to as Chromosomal Microarray Analysis – Comprehensive (CMA-COMP). Of the 3240 cases evaluated by this array, clinically significant CNVs were detected in 445 cases including 21 cases with exonic events. In addition, 162 cases (5.0%) showed at least one AOH region >10 Mb. We demonstrate that even though this array has a lower density of SNP probes than other commercially available SNP arrays, it reliably detected AOH events >10 Mb as well as exonic CNVs beyond the detection limitations of SNP genotyping. Thus, combining SNP probes and exon-targeted array CGH into one platform provides clinically useful genetic screening in an efficient manner.

Clinical performance of the CytoScan Dx Assay in diagnosing developmental delay/intellectual disability

“…However, obtaining AOH information in addition to copy-number information from the same platform is known to maximize the diagnostic yield from array testing. 14 …”

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…Since KMT2A is not targeted on the CdLS aCGH as a candidate gene, the CMA could investigate any potential pathogenic CNVs in the KMT2A locus and the entire genome. The array design and experimental procedures were described previously (24,57).…”

“…Agilent customized whole-genome array (BCM CMA version 9.1.1) was performed on patients WDSTS-1 and WDSTS-2 (24,58,59). Since KMT2A is not targeted on the CdLS aCGH as a candidate gene, the CMA could investigate any potential pathogenic CNVs in the KMT2A locus and the entire genome.…”

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

“…with intellectual disability has identified long regions of homozygosity (ROH) that were resolved into UPD events (Bruno et al 2011;Papenhausen et al 2011;Wiszniewska et al 2013). In addition, SNP data facilitates the detection of mosaic events by detecting minor allele fractions (B-allele frequencies) with systematic departures from diploid genotypes that are not associated with apparent copy number changes (Pique-Regi et al 2010;Van Loo et al 2010;Jacobs et al 2012).…”