Test Code: 4836

Chromosomal SNP Microarray: Prenatal testing
Test Code: 4836
Turnaround time: 2 weeks

CONDITION DESCRIPTION

Genetic imbalances such as chromosomal deletions and duplications have long been known to be a significant cause of intellectual disability, birth defects, developmental disorders, and pregnancy loss.  Traditional prenatal G-banded chromosome testing yields low-resolution structural and numerical analysis of the chromosomes.  The CEN4GEN Chromosomal SNP Microarray: Prenatal testing provides high-definition copy number analysis using the most current methods and software.  

Couples choosing prenatal diagnosis now have the option of microarray analysis to optimize detection of submicroscopic genetic imbalances.  To reduce parental concern during the testing process, we request parental blood or DNA samples to be submitted with the fetal sample. This speeds parental follow-up for genetic imbalances to determine if the finding(s) are de novo or inherited. Parental inheritance is important to consider when interpreting prenatal array findings.

Approximately 1.7% of women who have invasive prenatal testing due to advanced maternal age (AMA) or abnormal serum screening will have an abnormal chromosomal microarray finding that would be missed by traditional karyotype.1 This statistic rises to 6.0% for those pregnancies with structural fetal anomalies identified by ultrasound.1 In response to these new data, the American College of Obstetricians and Gynecologists (ACOG) issued a committee opinion on the use of chromosomal microarray analysis in prenatal diagnosis, which provided the following practice recommendations to replace those set in 2009:2

  • Chromosomal microarray analysis (CMA) is recommended for any patient undergoing an invasive diagnostic prenatal procedure because of the ultrasound indication of one or more major structural anomalies in the fetus. CMA replaces the need for fetal karyotype.
  • CMA or karyotype can be offered in those patients undergoing invasive diagnostic prenatal testing if no structural fetal abnormalities are noted on ultrasound regardless of maternal age.
  • CMA is recommended for products of conception in the case of intrauterine fetal demise or stillbirth.
  • Patients choosing CMA should receive both pre-test and post-test genetic counseling.
  • Since most abnormalities detected by CMA are not associated with AMA, the use of this test for prenatal diagnosis should not be restricted to women aged 35 years and older.

References:
1. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367:2175–8.
2. ACOG Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013 Dec; 122:1374–7.

INDICATIONS
This test is appropriate for any woman seeking prenatal detection of chromosomal imbalance. 

Common indications for prenatal diagnosis include:

  • Advanced maternal age
  • Abnormal maternal serum screen
  • Abnormal ultrasound
  • Family history of a genetic imbalance
  • Parental concern

Indications specific to the need for further testing by microarray:

  • Previous normal fetal karyotype with abnormal ultrasounds findings
  • Previous abnormal fetal karyotype showing an imbalance (excluding aneuploidies)
– For unbalanced rearrangements, microarray can be used to size the deletion or duplication and identify the genes involved.
  • Previous abnormal fetal karyotype showing an apparently balanced rearrangement

– For apparently balanced rearrangements, microarray can be used to test for cryptic deletions/duplications at the breakpoints.

METHODOLOGY
DNA isolated from the prenatal sample is hybridized to an array containing oligonucleotide and SNP probes across the genome to detect copy number imbalances and regions of homozygosity.

The CEN4GEN chromosomal SNP Array consists of 2.6 million markers (including 750,000 SNPs) which allows for the detection of both copy number variation (CNV) and large stretches [>10 Megabases (Mb)] of absence of heterozygosity (AOH), which can result from uniparental disomy (UPD) or common parental descent. The design is based on recommendations from the International Standards for Cytogenomic Arrays (ISCA) Consortium (Baldwin et al. (2008) Genet Med; 10(6):415-429).

DETECTION AND REFERENCE RANGE
Detection
This test detects trisomy, monosomy, chromosome deletions, and duplications. This test is designed to detect whole and partial chromosome UPD, multiple long stretches of absence of heterozygosity (AOH) greater than 3 Mb, and AOH in clinically relevant regions. In addition, this test can also detect triploidy, a common cause of miscarriages. Possible UPD will be reported when a chromosome has at least one homozygous regions >10 Mb. Homozygosity due to apparent common descent will be reported when >5% of the autosomal genome is present in long stretches of AOH. These regions of AOH will be specified to consider recessive risk alleles.This test will not detect balanced translocations, balanced inversions, imbalances smaller than the resolution of this array, point mutations, or low level mosaicism (usually less than 25%).

Reference Range
N/A

SPECIMEN REQUIREMENTS
Type: Parental specimen
A maternal blood sample is REQUIRED to rule out maternal cell contamination. It is also recommended to send a paternal blood sample to determine the parental inheritance of microarray findings of uncertain clinical significance. This reduces the wait time for the final interpretation of a prenatal result. Submit 5cc of maternal and paternal whole blood samples in EDTA tubes, or 20 to 60 ug of maternal and paternal DNA, together with only 1 prenatal specimen type below.

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample overnight at room temperature for receipt at CEN4GEN within 24 hours of collection.

Type: Chorionic Villi
Specimen Requirements:
5 to 10 ug of DNA in TE buffer.

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample overnight at room temperature for receipt at CEN4GEN within 24 hours of collection.

Type: Amniotic Fluid
Specimen Requirements:
5 to 10 ug of DNA in TE buffer.

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample overnight at room temperature for receipt at CEN4GEN within 24 hours of collection.

Type: Cord blood
Specimen Requirements:
5 to 10 ug of DNA in TE buffer.

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample overnight at room temperature for receipt at CEN4GEN within 24 hours of collection.