Increasing use of microarrays for genetic analysis of children

28 May 2010

The International Standard Cytogenomic Array (ISCA) Consortium has published a consensus statement in support of the use of chromosomal microarray (CMA) as a first line standard approach for the genetic evaluation of children with a range of disorders including developmental delay or intellectual disability (in the UK often termed learning disability), autism spectrum disorders, or multiple congenital anomalies (birth defects). These conditions account for a relatively large proportion of genetic testing as collectively they are relatively common.  CMA is a broad term encompassing ‘all types of array-based genomic copy number analyses, including array-based comparative genomic hybridization (aCGH)’.

The paper in the American Journal of Human Genetics presents the findings of a literature review of a total of 33 studies of CMA in nearly 22,000 people, comparing the technique with the current ‘gold-standard’ investigative approach of G-banded karyotyping [Miller DT et al. (2010) Am J Hum Genet. 86(5):749-64]. The study found that using microarray analysis increased diagnosis of chromosomal abnormalities underlying otherwise unexplained cases of learning disability, autism spectrum disorder or multiple congenital anomalies from around 3% for karyotyping to 15-20%. This is because the technique is able to detect small-scale (submicroscopic) chromosomal rearrangements that would not be visible from karyotyping, although the latter technique is better able to detect some rarer forms of abnormality (balanced rearrangements mosaicism than CMA.
The ISCA Consortium, which also held two international workshops on the subject as part of their investigation, concluded that CMA should therefore be used as a first-line approach for investigating such cases, although karyotyping should still be used for initial investigation of cases where there are strong medical reasons to suspect larger-scale chromosomal abnormalities – family history of chromosomal disorders or recurrent miscarriages (which often result from underlying chromosomal problems).
A second paper in the same journal reports a health economic analysis of the use of array genomic hybridization (aCGH or arrayCGH) compared with conventional karotyping for the detection of choromosmal causes of learning disability found that  despite the greater expense of aCGH, using the technique as a first line test was cost-effective, whereas using it only after karyotyping analysis was not [Regier DA, Friedman JM, Marra CA (2010). Am J Hum Genet. 86(5):765-72].

Comment: These conclusions are broadly in line with UK findings; the PHG Foundation originally worked with the UK Genetic Testing Network (UKGTN) to analyse the potential for using arrayCGH for the diagnosis of learning disability. The 2006 report, Evaluation of array-CGH for chromosomal abnormalities in clinical practice, was subsequently updated with systematic reviews of new evidence on this subject for the UKGTN; the latest review also suggested an increased diagnostic yield from the use of arrayCGH for patients with learning disability and congenital anomalies, but drew attention to the high rates of false positive diagnosis and the need for caution in clinical practice [Sagoo GS et al. (2009) Genet Med. 2009 Mar;11(3):139-46]. The ISCA is currently developing a public database of clinical CMA data over the nest two years to help develop clinical guidelines and software for interpretation of CMA tests (see Medical News Today).

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