Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features

TLDR

Many patients with learning disability and dysmorphic features have unidentified causes, and routine karyotype analysis fails to detect subtle chromosome rearrangements smaller than 5 Mb. The study aims to establish array‑CGH as a routine genome‑wide screening tool for imbalanced rearrangements in children with learning disability. Array‑CGH was performed on 50 patients using a 1‑Mb spaced DNA microarray of large insert clones to detect subtle copy‑number changes. Array‑CGH identified 12 copy‑number abnormalities in 12 of 50 patients (24 %): seven deletions (six de novo, one inherited) and five duplications (one de novo, four inherited), with sizes ranging from a single clone to 14 Mb, and no recurrent events were observed.

Abstract

The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less than 5 Mb). The presence of subtle DNA copy number changes was investigated by array-CGH in 50 patients with learning disability and dysmorphism, employing a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Twelve copy number abnormalities were identified in 12 patients (24% of the total): seven deletions (six apparently de novo and one inherited from a phenotypically normal parent) and five duplications (one de novo and four inherited from phenotypically normal parents). Altered segments ranged in size from those involving a single clone to regions as large as 14 Mb. No recurrent deletion or duplication was identified within this cohort of patients. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in children with learning disability.