Chromosomal Microarray Analysis (CMA)

Chromosomal Microarray Analysis (CMA) is a new genetic test that in conjunction with cytogenetic analysis is very useful in the evaluation of individuals with mental retardation. CMA uses a DNA chip and comparative genomic hybridization (CGH) to test for increased or decreased dosage of more than 60 chromosomal regions of known significance. With a single test, CMA can detect genomic errors for each of the disorders that are usually identified by cytogenetic analysis and multiple FISH tests including telomere FISH. Probes for all known microdeletion/ duplication syndromes and all telomeres are included in CMA. Although CMA will detect disorders such as trisomies, isodicentric 15 (also known as inverted duplication 15), 47XYY, 47XXY, and 47XXX, it is currently recommended that a routine Giemsa banded karyotype be performed prior to or simultaneous with ordering the CMA test. CMA will provide a major advance in the testing of patients in which a genetic cause of disability is suspected but not confirmed by traditional methods.

Advantages Of CMA In Testing Of Patient With Mental Retardation Disorders

1. Tests for virtually all disorders that are ordinarily screened for by individual FISH tests. Eliminates the need to request locus specific FISH tests individually.
2. Provides a superior alternative to telomere FISH. Telomere FISH is a test of proven value in the identification of genomic errors associated with developmental disabilities/mental retardation.
3. Detects duplications of common microdeletion regions (these duplications will not be detected by metaphase FISH, but are easily detected by CMA). Especially will detect interstitial duplications of 17p11.2 (the Smith-Magenis region) and 22q11.2 (DiGeorge/Velocardiofacial syndrome region), which have been associated with mental retardation.

Patients found to have a deletion/duplication by CMA will have the finding confirmed using conventional cytogenetics and/or FISH at no additional cost.

Recommendations For CMA Testing In Individuals With Mental Retardation

Initial studies suggest that of individuals referred for routine cytogenetic studies who had a normal karyotype, approximately 8% had a pathologic abnormality detected on CMA testing.

Recommendations for cytogenetic testing have been published in late 2005 (see www.acmg.net under ACMG Resources – Policy Statements and Practice Guidelines). Based upon these recommendations and a CMA detection rate that is higher than telomere FISH, CMA should be considered in an individual with mental retardation. This may be done in conjunction with routine cytogenetic analysis or this testing may be done sequentially. Whatever selections from available genetic test methodologies are chosen, note that retardation is a complex clinical challenge. The information which CMA and other tests provide must be compiled carefully, with medical perspective, in conjunction with medical personnel trained in their use, value, and limitations.

References:

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2. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, Winter RM, Bolton P, Flint J. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999 13;354:1676-81. PMID: 10568569

3. Knight SJ, Lese CM, Precht KS, Kuc J, Ning Y, Lucas S, Regan R, Brenan M, Nicod A, Lawrie NM, Cardy DL, Nguyen H, Hudson TJ, Riethman HC, Ledbetter DH, Flint J. An optimized set of human telomere clones for studying telomere integrity and architecture. Am J Hum Genet. 2000 67:320-32. PMID: 10869233

4. Portnoi MF, Lebas F, Gruchy N, Ardalan A, Biran-Mucignat V, Malan V, Finkel L, Roger G, Ducrocq S, Gold F, Taillemite JL, Marlin S. 22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes. Am J Med Genet. 2005 137(1):47-51. PMID: 16007629

5. Shaffer LG; American College of Medical Genetics Professional Practice and Guidelines Committee. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. 2005 Genet Med 7(9):650-654. PMID: 16301868