Extending the scope of diagnostic chromosome analysis: Detection of single gene defects using high-resolution SNP microarrays

Abstract

Microarray analysis has provided significant advances in the diagnosis of conditions resulting from submicroscopic chromosome abnormalities. It has been recommended that array testing should be a "first tier" test in the evaluation of individuals with intellectual disability, developmental delay, congenital anomalies, and autism. The availability of arrays with increasingly high probe coverage and resolution has increased the detection of decreasingly small copy number changes (CNCs) down to the intragenic or even exon level. Importantly, arrays that genotype SNPs also detect extended regions of homozygosity. We describe 14 examples of single gene disorders caused by intragenic changes from a consecutive set of 6,500 tests using high-resolution SNP microarrays. These cases illustrate the increased scope of cytogenetic testing beyond dominant chromosome rearrangements that typically contain many genes. Nine of the cases confirmed the clinical diagnosis, that is, followed a "phenotype to genotype" approach. Five were diagnosed by the laboratory analysis in the absence of a specific clinical diagnosis, that is, followed a "genotype to phenotype" approach. Two were clinically significant, incidental findings. The importance of astute clinical assessment and laboratory-clinician consultation is emphasized to optimize the value of microarrays in the diagnosis of disorders caused by single gene copy number and sequence mutations.

Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping

“…The LCSH data facilitated the identification of a pathogenic, homozygous sequence mutation that confirmed the clinical diagnosis of a specific monogenic disorder in four cases (described in detail in Bruno et al 21). The LCSH encompassing the causative sequence mutation(s) ranged in size from 2.2 megabases to 17 megabases.…”

High resolution array in the clinical approach to chromosomal phenotypes

“…The power of shifting the cytogenetic approach to the identification of monogenic dominant or recessive causes of developmental disorders by high resolution SNP technology up to an additional detection rate of about 0.2% has been recently demonstrated (Bruno et al, 2011). The current progress in the use of high-throughput sequencing technologies, however, and the realistic perspective of its introduction in a clinical setting may promise a superior approach.…”

Case of Sjögren–Larsson syndrome with a large deletion in the ALDH3A2 gene confirmed by single nucleotide polymorphism array analysis

“…The four previously reported large deletions were identified in Pakistan, India, England and Germany. 9,10,14 The 67-kb deletion identified here in our patient is a novel mutation detected by SNP array analysis from Saudi Arabia.…”