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Chromosomal Microarray, Postnatal, ClariSure Oligo-SNP

Chromosomal Microarray, Postnatal, ClariSure Oligo-SNP

Test Summary

Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP

  

Clinical Use

Postnatal Oligo-SNP Gene Targets

  • Determine the genetic etiology of developmental delay, intellectual disability, autism spectrum disorders (ASDs; pervasive developmental disorders), and multiple congenital anomalies

  • Confirm or exclude the diagnosis of known chromosomal syndromes

  • Further define ambiguities arising from cytogenetic or FISH studies

  • Assist in clinical management and genetic counseling

Clinical Background

Global developmental delay, intellectual disability (mental retardation), ASDs, and multiple congenital anomalies may be caused by environmental factors, genetic factors, or a combination of both. Determining the cause is important for long-term patient management and genetic counseling. Chromosomal abnormalities such as copy number variants (CNVs) are known to cause developmental delay and intellectual disability.1 CNVs are also estimated to occur in 8% to 21% of patients with ASDs.2 Chromosomal microarray (CMA) testing is a powerful method of identifying CNVs, many of which are associated with clinically actionable conditions.3

The American College of Medical Genetics (ACMG) recommends CMA testing as a first-line genetic test for developmental delay, intellectual disability, ASDs, and multiple congenital anomalies.2,4 This recommendation is based, in part, on a literature review that included over 21,000 patients with developmental delay/intellectual disability, ASDs, or multiple congenital anomalies. The diagnostic yield was 15% to 20% for CMA testing versus ~3% for G-banded karyotyping and ~6% for subtelomeric fluorescence in situ hybridization (FISH) in combination with G-banded karyotyping.5 In individuals with complex ASDs, CMA testing can result in a diagnostic yield of over 25%.2 ACMG still considers karyotyping a first-line test when patients are suspected of having a recognizable chromosomal syndrome such as trisomy 21 or 18, Turner syndrome, or Klinefelter syndrome.2,4

The oligonucleotide-single nucleotide polymorphism (oligo-SNP) array contains over 2.6 million probes and covers regions of known and likely CNVs. It can confirm the diagnosis of suspected disorders associated with known chromosomal syndromes and is especially well suited for determining the genetic cause of less well-described disorders. The oligo-SNP format provides extensive information across the genome allowing precise definition of breakpoints and detection of uniparental disomy, copy number neutral regions of homozygosity (ROH), and, in some cases, consanguinity.

Refer to the Table for a list of genes and associated disorders.

Table. Selected Genes and Associated Disorders in the Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP Test

Individuals Suitable for Testing

  • Individuals with unexplained developmental delay, intellectual disability, ASDs, or multiple congenital anomalies

Method

  • DNA preparation

   DNA extraction and digestion by restriction enzymes

–   Selective polymerase chain reaction (PCR) amplification of digested DNA

–   Purification and fragmentation of amplified DNA

  • Hybridization to the oligo-SNP microarray

   ~750,000 SNP probes for genotyping (copy number neutral event detection, eg, ROH) and CNV

detection

–   1.9 million copy number probes evenly spaced across the genome for CNV detection

  • Microarray analysis

   Software comparison of fluorescence scans of patient DNA with reference DNA data

–   Determination of copy number gains/losses and copy number neutral ROH

–   FISH probes may be used for confirmation of deletions

  • Resolution set at >50 kb for copy number loss and >200 kb for copy number gain

  • Results reported by a board-certified geneticist; include an ISCN description6 of any genomic abnormality detected and a clinical interpretation. CNVs known to have no phenotypic consequences are not reported.

Interpretive Information

The presence of specific chromosomal alterations previously associated with developmental delay, intellectual disability, ASDs, or multiple congenital anomalies suggests that these findings are most likely the cause of the respective disorder. Findings with uncertain clinical significance (equivocal findings) may be followed up with parental testing to help distinguish pathogenic from benign results. A CNV is more likely to be pathogenic if the same CNV is detected in an affected parent; conversely, a CNV is more likely to be benign if it is detected in an unaffected parent.5 Other clinical situations may also require follow-up with parental testing.

Although the array provides extensive information across the genome, normal results do not rule out the possibility of chromosomal abnormalities. This assay may not detect rearrangements that do not result in a gain or loss of genetic material (eg, balanced reciprocal translocations or inversions) or mosaic abnormalities or aberrations smaller than the resolution of the array. The array effectively genotypes SNPs across the genome, but it will not detect point mutations or other alterations at the single gene level for the purposes of carrier or mutational analysis for any particular disease.

Additional assistance in interpretation of results is available from Quest Diagnostics Genetic Counselors by calling 866-GENE-INFO (866-436-3463).

References

  1. 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. Genet Med. 2005;7:650-654.

  2. Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399-407.

  3. Ellison JW, Ravnan JB, Rosenfeld JA, et al. Clinical utility of chromosomal microarray analysis. Pediatrics. 2012;130:e1085-1095.

  4. Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742-745.

  5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749-764.

  6. Shaffer LG, McGowan-Jordan J, Schmid M, eds. ISCN 2013: An International System for Human Cytogenetic Nomenclature (2013). Basel, Switzerland: S. Karger AG; 2013.
     

This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Content reviewed 11/2013

 
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