CLINICAL ACTIONS:

Chromosomal microarray (also known as CMA) technology has revolutionized the practice of genetics and is now commonly ordered prenatally and throughout the lifespan.  Structural chromosomal anomalies, once too small to be ‘seen’ using conventional karyotyping, can now be detected using molecular techniques.  Microarrays can detect copy number variants (CNVs) and therefore identify chromosomal regions where there is excess DNA (a duplication) or missing DNA (a deletion).

Consider the following when counseling:

Benefits of Microarrays

Prenatal detection of clinically significant CNVs that would have been missed using conventional karyotyping alone

• 6% of abnormal fetuses with a normal karyotype may have pathogenic CNVs or likely pathogenic CNVs
  • Isolated finding: 5.6%
  • Multiple anomalies: 9.1%
• 1.7% of normal fetuses and normal karyotype may have pathogenic CNVs or likely pathogenic CNVs

Postnatal detection of significant CNVs that would have been missed using conventional karyotyping alone

• Developmental delay and intellectual disability
  • An additional 12.2% – 19% pathogenic anomalies May be detected with the addition of microarray

Can be performed on tissue that is no longer viable

• If DNA is present and of sufficient quality, test can be run on stillbirth specimens or products of conception

Limitations of Microarrays

Balanced translocations

• Balanced translocations occur in approximately 1/500 individuals and are usually benign
• Because there is minimal/no additional or deleted genetic material, balanced translocations will go undetected with microarray but depending on size, may be seen with conventional karyotyping
• Serious consequences are still possible with balanced translocations due to breakpoints disrupting genes
  • ACMG (2018) notes the importance of balanced rearrangements (e.g., translocation, inversion, insertion) and states that “recurrence risk counseling is indicated for offspring of parent with a balanced rearrangement
  • Estimated additional diagnostic yield of 0.78 to 1.3% if a G-banded karyotype is performed following a negative microarray

Single gene disorders

• May be caused by a single or small base pair change and will not be detected on microarray

Variants of uncertain significance (VUS)

• Can occur in 1 to 2% of cases
• May cause parental anxiety and will require additional expert counseling and follow-up
• Over time, VUSs are being categorized as benign or pathogenic as additional reports are incorporated into databases

SYNOPSIS:

The data from a major NICHD study in 2012 provided the support for introducing microarray technology into prenatal clinical care, with previous studies highlighting the benefits in the postnatal period and beyond.  Similar to a conventional karyotype, microarrays can detect aneuplodies and larger structural chromosomal changes. In addition, microarray technology allows for the identification of small duplications and microdeletions that would otherwise go unreported. There are limitations and expert counseling is required to provide optimal care and informed decision making.

KEY POINTS:

Prenatal Recommendations

SMFM

• Fetal structural anomalies on prenatal ultrasound or stillbirth
  • Microarray replaces conventional karyotype (1A)
• Patient undergoing invasive testing and no anomalies identified
  • Both options, conventional karyotype and microarray, should be discussed (1B)

SOGC & CCMG

• Microarray should be offered following a normal rapid aneuploidy screen when
  • Multiple fetal malformations are detected (II-1A) or
  • NT ≥3.5 mm (II-2B)

Postnatal Recommendations

ACMG

• Microarray is a first-line test in the initial postnatal evaluation in the following clinical scenarios
  • Multiple anomalies not specific to a well-delineated genetic syndrome
  • Apparently nonsyndromic developmental delay/intellectual disability
  • Autism spectrum disorders
• There may be a role in other less well-studied indications and further study is recommended

NOTE: Professional bodies universally recommend expert pre- and post-test counseling whenever microarray is being considered

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Learn More – Primary Sources:

ACOG/ SMFM Committee Opinion 682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology

SMFM: The use of chromosomal microarray for prenatal diagnosis

ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013

Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG 2018)

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

NEJM (2012): Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis

Related ObG Topics:

Microarrays and Microdeletions: Key Concepts Summarized

NIPS vs. Microarray for Pathogenic Results

Can NT Values be Used as an Indication for Prenatal Microarray Analysis?

Should Amniocentesis or Chorionic Villus Sampling Be Offered to All Pregnant Women?