Chromosomal Microarray Analysis (CMA)

Chromosomal Microarray Analysis (CMA) is a new genetic test that has major advantages over existing karyotypic testing. 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/dup-lication 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.

Advantages Of CMA In Testing For Disorders Manifesting Autistic Features

1. There are increasing reports that de novo deletions and duplications are the cause of autism in 10-15% of patients (See Vorstman et al., Jacquemont et al., and Sebat et al. below.)
2. Tests for virtually all disorders that are ordinarily screened for by individual FISH tests. Eliminates the need to request specific FISH tests individually.
3. 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.
4. Detects duplications of regions commonly detected to be deleted by FISH, but metaphase FISH does not detect duplications. Especially will detect interstitial duplications of 15q11-q13 (the Prader-Willi/Angelman region and 17p11.2 (the Smith-Magenis region). Both of these duplications have been found in individuals with clinical features of autism, and until now, testing for these duplications has only been available on a research basis.

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

Caution

All known genetic tests will be normal in the great majority (perhaps 80-90%) of patients with various forms of clinical autism. 

In 5 to 10 % of patients with clinical autism, genetic testing will detect a specific genetic abnormality such as fragile X syndrome. Karyotypic analysis will detect conditions such as sex chromosome abnormalities (i.e. XXY, XYY, XXX) and isodicentric 15q. 

In 2-5% of patients, the CMA test can identify small chromosomal deletions and duplications not detectable by karyotype. These DNA abnormalities, which CMA can detect, are exhibited to a greater degree in children with clinical mental retardation and associated minor congenital abnormalities as compared to higher functioning children who appear physically normal. 

CMA is not a general test for autism.  CMA is not appropriate as a prenatal test for autism. 

Other Genetic Testing for Patients with Autistic Features

Widely recommended genetic tests used in the evaluation of autism:

1. Routine Giemsa banded karyotype
2. Plasma quantitative amino acid analysis
3. Urine organic acid analysis
4. DNA analysis for fragile X syndrome
5. Telomere FISH (CMA would replace this)

Tests recommended by some experts:

1. Chromosomal microarray analysis
2. Urine purine profile
3. Blood homocysteine level
4. Possibly Rett mutation testing in selected cases

Routine, less specialized tests:

1. Comprehensive serum chemistry (preprandial)
2. Routine urine analysis
3. Blood lactate and pyruvate

References:

1. Vorstman JA, Staal WG, van Daalen E, van Engeland H, Hochstenbach PF, Franke L. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry. 2006 Jan;11(1):1, 18-28. Review. PMID: 16205736
2. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M. Strong Association of De Novo Copy Number Mutations with Autism. Science. 2007 Mar 15; [Epub ahead of print] PMID: 17363630
3. Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S, Amiel J, Le Merrer M, Heron D, de Blois MC, Prieur M, Vekemans M, Carter NP, Munnich A, Colleaux L, Philippe A. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet. 2006 Nov;43(11):843-9. Epub 2006 Jul 13. PMID: 16840569
4. Lauritsen M, Mors O, Mortensen PB, Ewald H. Infantile autism and associated autosomal chromosome abnormalities: a register-based study and a literature survey. J Child Psychol Psychiatry. 1999 40:335-45. PMID: 10190335
5. Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol. 2003 28:205-11. PMID: 12770674
6. Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997 60:928-34. PMID: 9106540
7. Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevenson RE. Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet. 1998 76:327-36. PMID: 9545097
8. Moog U, Engelen JJ, Weber BW, Van Gelderen M, Steyaert J, Baas F, Sijstermans HM, Fryns JP. Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12). Genet Couns. 2004 15:73-80. PMID: 15083703
9. Goizet C, Excoffier E, Taine L, Taupiac E, El Moneim AA, Arveiler B, Bouvard M, Lacombe D. Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. Am J Med Genet. 2000 4;96:839-44. PMID: 11121193
10. Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, Bobrow M, Carter NP. Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet. 2004 41:241-8. PMID: 15060094
11. Keller K, Williams C, Wharton P, Paulk M, Bent-Williams A, Gray B, Ward A, Stalker H, Wallace M, Carter R, Zori R. Routine cytogenetic and FISH studies for 17p11/15q11 duplications and subtelomeric rearrangement studies in children with autism spectrum disorders. Am J Med Genet. 2003 117A:105-11. PMID: 12567405