High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results

Abstract

Background: Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however.

Methods and results: Using the Genome-Wide Human SNP array 6.0, we analyzed 35 patients with a developmental disorder of unknown cause and normal array comparative genomic hybridization (array CGH) results, in order to characterize previously undefined genomic aberrations. We detected no seemingly pathogenic copy number aberrations. Most of the vast amount of data produced by the array was polymorphic and non-informative. Filtering of this data, based on copy number variant (CNV) population frequencies as well as phenotypically relevant genes, enabled pinpointing regions of allelic homozygosity that included candidate genes correlating to the phenotypic features in four patients, but results could not be confirmed.

Conclusions: In this study, the use of an ultra high-resolution SNP array did not contribute to further diagnose patients with developmental disorders of unknown cause. The statistical power of these results is limited by the small size of the patient cohort, and interpretation of these negative results can only be applied to the patients studied here. We present the results of our study and the recurrence of clustered allelic homozygosity present in this material, as detected by the SNP 6.0 array.

Figure 1

Frequency of CNVs and allelic homozygosity. The figure visualizes the frequency of copy number changes (loss and gain) and regions of allelic homozygosity (LOH) in 70 patients (patients of this study N = 35 and the in-house reference set N = 35) with developmental disorders of unknown cause as seen by the Integrative Genomics Viewer (IGV) software V.1.5 (The Broad Institute, Cambridge, MA, USA). The vertical bars show the percentage of patients that have a CNV in a particular area of a chromsome. The higher the bar, the higher the percentage, thus indicating as CNP.