Whole‐genome array‐CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features

Abstract

Cytogenetic imbalances are the most frequently identified cause of developmental delay or mental retardation, which affect 1-3% of children and are often seen in conjunction with growth retardation, dysmorphic features, and various congenital anomalies. A substantial number of patients with developmental delay or mental retardation are predicted to have cytogenetic imbalances, but conventional methods for identifying these imbalances yield positive results in only a small fraction of these patients. We used microarray-based comparative genomic hybridization (aCGH) to study a panel of 20 patients predicted to have chromosomal aberrations based on clinical presentation of developmental delay or mental retardation, growth delay, dysmorphic features, and/or congenital anomalies. Previous G-banded karyotypes and fluorescence in situ hybridization results were normal for all of these patients. Using both oligonucleotide-based and bacterial artificial chromosome (BAC)-based arrays on the same panel of patients, we identified 10 unique deletions and duplications ranging in size from 280 kb to 8.3 Mb. The whole-genome oligonucleotide arrays identified nearly twice as many imbalances as did the lower-resolution whole-genome BAC arrays. This has implications for using aCGH in a clinical setting. Analysis of parental DNA samples indicated that most of the imbalances had occurred de novo. Moreover, seven of the 10 imbalances represented novel disorders, adding to an increasing number of conditions caused by large-scale deletions or duplications. These results underscore the strength of high-resolution genomic arrays in diagnosing cases of unknown genetic etiology and suggest that contiguous genomic alterations are the underlying pathogenic cause of a significant number of cases of developmental delay.

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

“…Nevertheless, the diagnostic yield for all current CMA is estimated at 12% for patients with GDD/ID. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] CMA is the single most efficient diagnostic test, after the history and examination by a specialist in GDD/ID.…”

Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects

“…Twelve studies were identified since the publication of our previous meta-analysis. [21][22][23][24][25][26][27][28][29][30][31][32] Seven studies were conducted on patients based in the United States, [21][22][23]25,28,31,32 seven in Europe, 6,15,17,18,24,29,30 four using patients from multiple sources based in North America, South America, or Europe 19,20,26,27 and one in Japan. 16 All studies included sampling of control DNA as part of their protocol.…”

“…16 All studies included sampling of control DNA as part of their protocol. Seven studies used a 1 Mb array for investigating the whole genome, 6,15,18 -20,22,29 four used a targeted array, 16,26,27,31 three used an oligonucleotide array with 30 -35 k resolution, 21,25,28 two studies used a 100-k array, 23,30 one used a tiling BAC array, 17 one study used both a targeted array and a 1-Mb array, 32 and another used a 1-Mb array supplemented with an additional 3000 gene and region-specific BAC clones increasing the resolution to 0.5 Mb. 24 Control samples varied from 2 to 316 normal people, whereas Menten et al 15 used samples from other patients in the cohort as controls.…”

Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray

“…37,38 This technology has been used in the detection of chromosomal imbalances associated with MR or autism. 39,40 However, these commercial arrays were not designed specifically for clinical cytogenetics applications, and therefore may not have adequate density and coverage for clinically relevant regions, such as telomeres, centromeres and microdeletion or microduplication syndromes. 41,42 To overcome this deficiency, it is possible to design custom microarrays to enhance the coverage at clinically relevant regions.…”