High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?

Abstract

We used Affymetrix 6.0 GeneChip SNP arrays to characterize copy number variations (CNVs) in a cohort of 70 patients previously characterized on lower-density oligonucleotide arrays affected by idiopathic mental retardation and dysmorphic features. The SNP array platform includes B900 000 SNP probes and 900 000 non-SNP oligonucleotide probes at an average distance of 0.7 Kb, which facilitates coverage of the whole genome, including coding and noncoding regions. The high density of probes is critical for detecting small CNVs, but it can lead to data interpretation problems. To reduce the number of false positives, parameters were set to consider only imbalances 475 Kb encompassing at least 80 probe sets. The higher resolution of the SNP array platform confirmed the increased ability to detect small CNVs, although more than 80% of these CNVs overlapped to copy number 'neutral' polymorphism regions and 4.4% of them did not contain known genes. In our cohort of 70 patients, of the 51 previously evaluated as 'normal' on the Agilent 44K array, the SNP array platform disclosed six additional CNV changes, including three in three patients, which may be pathogenic. This suggests that about 6% of individuals classified as 'normal' using the lower-density oligonucleotide array could be found to be affected by a genomic disorder when evaluated with the higher-density microarray platforms.

Establishing genetic diagnosis of intellectual disability in children: diagnostic yield of various genetic approaches

“…Lately, however, genetic aetiology has been determined for more and more ID / DD cases, especially in developed countries. Within our investigation we have discovered genetic testing to be informative only for a percentage (40.5%) of all ID / DD patients, which is in line with similar studies where genetic predisposition is reported in 17-47% of cases (5,10). According to our results, the genetic diagnosis was most commonly established in infancy and in more severely affected patients, when besides ID / DD, congenital anomalies and dysmorphic features were present.…”

“…However, at present specific aetiology can only be described in about 50% of the cases, while the rest remains elusive (5). Combined data from a number of related studies suggest that about 17-47% of all ID / DD cases could be attributed to genetic abnormalities (6).…”

Genome Arrays for the Detection of Copy Number Variations in Idiopathic Mental Retardation, Idiopathic Generalized Epilepsy and Neuropsychiatric Disorders: Lessons for Diagnostic Workflow and Research

“…The limited contribution of an increment in the number of probes to ϳ 500,000 is also illustrated by the finding of Friedman et al [2009] that among 44 MR/MCA patients who tested negative on a 100,000 SNP genotyping platform, only 1 tested positive when all 44 were reanalyzed using a 500,000 SNP platform. Similarly, Bernardini et al [2009] reanalyzed 51 patients, who scored normal using a 44,290 oligonucleotide array-CGH platform, on a SNP genotyping platform containing 1,800,000 probes, and a pathogenic imbalance was detected in only 3 of these patients. It seems, therefore, that the position of the probes relative to dosagesensitive regions of the genome is more critical than probe number.…”

Pathologic Genomic Rearrangements in Idiopathic Mentally Retarded Patients from Iran

“…Causes of mental retardation are numerous and include genetic and environmental factors [4]. Anything that damages and interferes with the growth and maturation of the brain can lead to MR, and this might happen before, during or after the birth of the child [1,3]. Though it is generally assumed that half of the cases are due to genetic factors, the cause of the handicap in up to 50% of patients remains unexplained [5].…”

“…MR etiology is very heterogeneous and unfortunately, in about more than half the cases the cause of MR is still elusive [3]. Causes of mental retardation are numerous and include genetic and environmental factors [4].…”