Cytogenomic SNP Microarray

  • Preferred first-tier test for DD/ID, ASD, and/or MCAs
  • Testing is performed on peripheral blood
  • Same test as the Cytogenomic SNP Microarray, except testing is performed on a buccal specimen
  • Requires a buccal swab using Oracollect collection kit
Related Tests
  • Cytogenomic SNP Microarray is performed concurrently with a limited 5-cell chromosome study
  • Useful when chromosome and array tests would otherwise have been ordered concurrently
  • Chromosomes are useful to characterize the structure of some abnormalities; genomic microarray does not provide this characterization
  • Less sensitive for mosaicism detection than standard 20-cell chromosome study
  • Appropriate when aneuploidy is suspected
  • Chromosome analysis will identify:
    • Numerical abnormalities
    • Most balanced chromosomal rearrangements
    • Large deletions/duplications
  • If chromosomes are normal, testing reflexes to genomic microarray

Cytogenomic SNP microarray testing is the recommended first-tier test for individuals with developmental delay (DD), intellectual disability (ID), multiple congenital anomalies (MCAs), and/or autism spectrum disorder (ASD)/pervasive developmental disorder (PDD). Microarray testing can further characterize chromosomal abnormalities, including marker or ring chromosomes, deletions or duplications, unbalanced translocations and inversions. Regions of homozygosity (ROH) can also be identified.

DISEASE OVERVIEW

Prevalence

  • Global DD/ID: 1-3%
  • ASD: 1-2%

Diagnostic Issues

  • Many abnormal phenotypes are associated with chromosomal imbalances
  • Chromosome analysis has limited ability to detect small, cryptic abnormalities (<10–20 Mb)
  • Genomic microarray can detect chromosomal imbalances at a much higher level of resolution than standard chromosome analysis
  • Genomic microarray can detect ROH, which may indicate an increased risk for autosomal recessive (AR) disease for genes contained within the ROH and/or the risk of an imprinting disorder due to uniparental disomy (UPD)
  • Identification of specific abnormalities may be helpful in medical management and planning for special needs

TEST INTERPRETATION

Diagnostic Yield

  • 15-20% for individuals with:
    • Unexplained ID
    • ASD
    • MCAs
  • The diagnostic yield varies by patient population and the presence of comorbidities

Results

  • A written summary and an interpretation of the microarray findings are provided.
  • Copy number variant (CNV) evaluation is performed in accordance with recommendations by the American College of Medical Genetics and Genomics (ACMG):
    • Standard five-tier classification terminology is used:
      • Pathogenic
      • Likely pathogenic
      • Variant of uncertain significance (VUS)
      • Likely benign
      • Benign
    • Variants that do not fall within these categories may be reported with descriptive language specific to that variant.
  • For a list of databases used in CNV classification, see the ARUP Cytogenomic Constitutional CNV Assertion Criteria. This and other resources can be found on the ARUP Genetics Resources website.
Result Description
Normal

No clinically significant CNV or ROH detected

Abnormal

One or more clinically significant CNV, ROH, or aneuploidy detected

Uncertain

One or more CNVs of uncertain clinical significance detected

  • Insufficient evidence for unequivocal determination of clinical significance available at the time of review

Risk for AR disease and/or imprinting disorder due to UPD

  • Testing may suggest relatedness between the parents of the tested individual

Reporting Criteria

  • Deletions >50 kb and duplications >400 kb are generally reported, dependent on genomic content
  • Total autosomal homozygosity >3% is generally reported
    • Only autosomal ROH >3 Mb are considered for this estimate
  • Single terminal ROH >3 Mb or single interstitial ROH >10-15 Mb are generally reported, dependent upon chromosomal location and likelihood of imprinting disorder
  • Recessive disease risk and recurrent CNVs with established reduced penetrance are generally reported
  • CNVs classified as likely benign or benign that are devoid of relevant gene content or reported as common findings in the general population are generally not reported

Limitations

  • Does not detect:
    • CNVs below the limit of resolution of the testing platform
    • Sequence-level variants (mutations) including point mutations and small insertions/deletions
    • Balanced chromosomal rearrangements (translocations, inversions and insertions)
    • Imbalances of the mitochondrial genome
    • Low-level mosaicism (generally <20-30%)