Cytogenomic SNP Microarray, Fetal

Cytogenomic SNP microarray testing is used to identify genomic imbalances (deletions and duplications) and may be used to further characterize abnormalities identified by chromosome analysis, including unbalanced translocations, recombinant chromosomes, markers, and ring chromosomes. Regions of homozygosity (ROH) can also be identified. It is the recommended first-tier test for patients undergoing prenatal diagnosis for the indication of a fetal structural abnormality detected by ultrasound (unless the structural abnormality is strongly suggestive of a specific aneuploidy, in which case, karyotype with or without fluorescence in situ hybridization [FISH] may be offered before genomic microarray).

Diagnostic Issues

• Many abnormal phenotypes are associated with chromosomal imbalances.
• Chromosome analysis has limited ability to detect copy number abnormalities less than 10-15 Mb in size.
• 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), or molar pregnancy.
• Identification of specific abnormalities may be helpful in medical management and planning for special needs.

Test Interpretation

Diagnostic Yield

• Among cases with a normal karyotype, microarray studies reveal clinically relevant copy number variants (CNVs) in:
  • Approximately 6% of fetuses with a structural anomaly; percentage may be higher, depending on anomaly
  • Approximately 2% whose indication is advanced maternal age or positive aneuploidy screen
• 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.
• CNV evaluation is performed in accordance with recommendations by the American College of Medical Genetics and Genomics (ACMG):
  • Standard 5-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 additional information regarding CNV classification, refer to the ARUP Constitutional Copy Number Variant Assertion Criteria.
  • Additional resources can be found on the ARUP Genetics Resources website.
• Submission of a maternal blood sample for maternal cell contamination studies is encouraged.

Reporting Criteria

• Deletions >1 Mb and duplications >2 Mb are generally reported, dependent on genomic content.
• CNVs classified as VUS are generally reported when found to have suspected clinical relevance based on information available at the time of review, or when meeting size criteria.
• Total autosomal homozygosity >5% is generally reported.
  • Only autosomal ROH >3 Mb are considered for this estimate.
• Single terminal ROH >3 Mb or single interstitial ROH >10-20 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.
• Known or expected pathogenic CNVs affecting genes with known clinical significance but which are unrelated to the indication for testing will generally be 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%)
  • Most cases of tetraploidy