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Pregnancy Loss Microarray


Test Options that Include Pregnancy Loss Microarray:

  • Chromosomal SNP microarray
  • Chromosomal SNP microarray and 5-cell chromosome analysis
  • Standard chromosome analyisis and if results normal, REFLEX to chromosomal SNP microarray on cultured cells

Single nucleotide polymorphism (SNP) based chromosomal microarray (CMA) is a powerful cytogenomic tool for detecting both copy number variation (deletions or duplications) and copy-neutral structural variants such as regions of homozygosity (ROH) and uniparental disomy (UPD). Detection of submicroscopic abnormalities, including microdeletions and microduplications, may be missed by standard chromosome analysis.

 
Features of the Infinium® CytoSNP-850K BeadChip Array 
  • High resolution array containing 850,000 SNPs with ~15x redundancy of each marker
  • Follows the International Standard Cytogenomic Arrays (ISCA) consortium guidelines for chip design
  • Features are spaced ~16 kb along the backbone of the genome
  • Probes spaced ~1.8 kb along genome for a resolution of ~10kb
  • Targets microdeletion/microduplication syndrome regions with enriched coverage for more than 3,200 known disease genes
  • Regions of homozygosity (ROH) evaluated for possible uniparental disomy (UPD) and recent shared ancestry
  • SNP CMA can detect triploidy
  •  

Indications
  • Spontaneous fetal loss at any gestational age
  • Induced termination due to fetal anomalies
  • Fetal loss with abnormal karyotype requiring further characterization
  • Fetal loss when conventional chromosome analysis cannot be obtained (due to culture failure)


If clinically relevant, common aneuploidies, such as Down syndrome or Trisomy 18, should be ruled out by chromosome analysis or fluorescence in situ hybridization (FISH) before CMA testing is pursued.

 

Methodology

DNA is obtained by extraction from fetal tissue, products of conception and/or placenta.  The CytoSNP-850K assay utilizes an amplification step for the DNA and hybridizes this to the BeadChip. The assay then uses a labeling process to provide allele and intensity data. BeadChips are scanned using a two-channel high-resolution laser imager and analyzed using Illumina software. 

For reporting of copy number variations (CNVs), thresholds are ≥1 Mb for deletions and ≥2 Mb for duplications with reporting of smaller findings in clinically significant regions. Common CNVs listed in the Database of Genomic Variants are not reported. While NOT diagnostic, SNP data allows for detection of regions of homozygosity (ROH) suggestive of UPD (isodisomy) or shared ancestry (consanguinity) with possible implications in the context of recessive disorders. ROH is evaluated at ≥5 Mb with a reporting threshold of ~10 MB. Total percentage of ROH is reported when ≥5%.

For the 5-cell chromosome analysis, a minimum of 5 metaphases are examined and 3 karyotypes are prepared at ≥400-450 band level (standard resolution).  In the routine/standard chromosome analysis, a minimum of 15 metaphase cells are counted and 3 karyotypes prepared.

 

Limitations

SNP CMA can detect whole genome mosaicism suggestive of two different genomic cell lines, as in the case of maternal cell contamination.  The presence of maternal cell contamination may limit the interpretation of CMA results.  For products of conception or placenta sample, when a single female genome is detected, it is assumed to represent the female fetus.  However, the rare possibility that the DNA analyzed is maternal in origin cannot be excluded.

CMA will not detect balanced rearrangements (i.e., inversions, translocations), heterodisomy, or very low level mosaicism.  It will not detect single gene mutations, such as single nucleotide mutations/polymorphisms. Abnormalities that are smaller than the resolution of the array may not be detected.

The cytogenetic analysis will not detect very subtle chromosomal rearrangements.  The 5-cell chromosome analysis will not adequately detect possible mosaicism.

 

Specimen Requirements

Fetal tissue is preferred in order to minimize the possibility of maternal cell contamination.

Fetal tissue (preferred)
  • Submit 0.5 cm3 fetal tissue in a sterile, plastic, screw-top tube filled with sterile transport media. CGL can provide this media.

  • If separate fetal and placental specimens are available, place each in separate tubes and label each tube with the specimen type.

  • Label specimen tubes with patient's name and a second identifier.

  • Hold specimen at room temperature and transport to the Colorado Genetics Laboratory as soon as possible. Refrigerate if held overnight.

 

Products of conception or placenta

  • Submit 0.5 cm3 products of conception or placenta in a sterile, plastic, screw-top tube filled with sterile transport media. CGL can provide this media.

  • If separate fetal and placental specimens are available, place each in separate tubes and label each tube with the specimen type.

  • Label specimen tubes with patient’s name and a second identifier.

  • Hold specimen at room temperature and transport to the Colorado Genetics Laboratory as soon as possible. Refrigerate if held overnight.

 
Samples must be accompanied by a completed Test Request Form​​ and Waiver for CytoSNP-850K Microarray. Indicate chromosomal microarray testing and include alll pertinent medical and family history.
 
Interpretation Services

Detailed written report provided with genetic counseling phone consultation available to medical providers.

 

Follow-Up Testing

Colorado Genetics Laboratory recommends that parental/familial testing be considered when a genomic imbalance is detected by chromosomal microarray. Please see current policy – Familial Follow-up After Abnormal Microarray Effective June 1, 2014.

 

Microarray Billing Policy Effective June 1, 2014

When the new molecular CPT codes became effective January 1, 2013, insurance companies subsequently revised their medical policies regarding medical necessity for chromosomal microarray. Because of the variability among these policies, waivers for microarray testing have been implemented for all insurance carriers, except Colorado Medicaid. Please have your patient complete and sign the Waiver for CytoSNP-850K Microarray form below, and submit it with the specimen for microarray testing. If the patient’s insurance denies the charges, the patient will be billed at a discounted rate.

 
References
  1. Kearney HM, et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 13:680-5, 2011.
  2. Reddy UM, et al., Karyotype versus Microarray Testing for Genetic Abnormalities after Stillbirth. The New England Journal of Medicine 367:23:2185-2193, 2013.
  3. South ST, et al. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 15:901-9, 2013.