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

Abstract

Array-based comparative genomic hybridization is being increasingly used in patients with learning disability (mental retardation) and congenital anomalies. In this article, we update our previous meta-analysis evaluating the diagnostic and false-positive yields of this technology. An updated systematic review and meta-analysis was conducted investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic analyses have proven negative. Nineteen studies (13,926 patients) were included of which 12 studies (13,464 patients) were published since our previous analysis. The overall diagnostic yield of causal abnormalities was 10% (95% confidence interval: 8 -12%). The overall number needed to test to identify an extra causal abnormality was 10 (95% confidence interval: 8 -13). The overall false-positive yield of noncausal abnormalities was 7% (95% confidence interval: 5-10%). This updated meta-analysis provides new evidence to support the use of array-based comparative genomic hybridization in investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic tests have proven negative. However, given that this technology also identifies false positives at a similar rate to causal variants, caution in clinical practice should be advised. Genet Med 2009:11(3):139 -146.

Clinical performance of the CytoScan Dx Assay in diagnosing developmental delay/intellectual disability

“…This diagnostic yield is comparable to previous reports of historical RPC, which often used microarrays to assess these patients, and it is also consistent with the published literature on diagnostic yield in this patient population. 4,5,15 This study was originally designed to meet US Food and Drug Administration requirements and the interpreting cytogeneticist did not have access to any complementary information, as is standard in laboratory analysis (i.e., clinical data or supplementary laboratory testing). To obtain a more realistic view of CytoScan Dx Assay's diagnostic yield, it may be useful to reanalyze this data set with the complete laboratory information available to a qualified cytogeneticist.…”

“…However, in recent years, with the advent of new techniques such as the chromosomal microarray (CMA), the yield has increased ~10-18%. 4,5 Additionally, it was recently reported by Shashi et al 6 that when a combination of laboratory tools including a microarray was used, 46% of patients suspected of having a genetic disease were diagnosed and 72% of these diagnoses were made on the first visit. The authors also showed that a genetic diagnosis in a patient leads to an average cost reduction of more than $1,435 in direct genetic laboratory tests (including number of visits to diagnosis and cost of all genetic tests performed) as compared with undiagnosed patients.…”

High prevalence of array comparative genomic hybridization abnormalities in adults with unexplained intellectual disability

“…Four genomic gains were also identified (Tables 2 and 3; Patients [11][12][13][14]. Three of these were initially suspected to be novel and potentially pathogenic; the fourth gain (Patient 13; Fig.…”

“…A recent meta-analysis of 19 large, well-designed studies of intellectual disability and congenital anomalies reported a clinically significant range of 6 -35% for genomic imbalance and an overall diagnostic yield estimate of 10%. 11 This study included data from 13,926 patients (range 20 -8789/study), and although detailed age data are not reported in all studies, the studied population includes large populations from referral laboratories where sample ascertainment frequently comes from pediatricians and pediatric geneticists. One study of more than 5000 cases had a median age of just 4 years.…”

Availability of treatment drives decisions of genetic health professionals about disclosure of incidental findings

“…1 A consequence of the untargeted nature of genomic tests is the increased likelihood of detecting an incidental finding (IF). The definition of an IF is variable, but in the context of genomic testing the term is used most commonly to describe a mutation that is detected but is unrelated to the original reason for testing.…”