Avoiding common cytogenetic ordering pitfalls

Advances in genetic testing have substantially improved the ability to detect chromosomal abnormalities. However, with multiple testing options available, it can be challenging to know which test is best suited for a particular clinical indication or question. Test orders that are not appropriate for the clinical indication can lead to incomplete answers, delayed diagnoses, and/or confusion when interpreting results. 

This blog discusses the top three scenarios of misorders for cytogenetic tests:

1. Chromosomal microarray and recurrent pregnancy loss
2. Chromosomal microarray and trisomy recurrence risk
3. Chromosomal microarray and single-gene disorders

Understanding what each cytogenetic test can and cannot detect is crucial in selecting the most appropriate testing option. The two cytogenetic tests discussed in this blog are chromosome analysis and chromosomal microarray:

• Chromosome analysis (also known as karyotyping)—allows visualization of whole chromosomes and can detect large rearrangements (~5-10 Mb), such as balanced translocations
• Chromosomal microarray (CMA)—detects extra or missing pieces of chromosomal material at a higher resolution (~50-200 kb) than a karyotype but cannot determine how that material is arranged

Recurrent pregnancy loss is a common indication for genetic testing. Individuals with a balanced translocation are typically healthy (and may be unaware they carry a rearrangement) but can have a pregnancy with unbalanced chromosomal material, which can result in miscarriage.

Common pitfall: Ordering only CMA to test individuals with recurrent pregnancy loss because of its ability to detect small gains and losses of genetic material. CMA cannot detect balanced chromosome rearrangements, so a normal CMA result would not rule out a parent carrying a balanced translocation.

Recommendation: Order blood chromosome analysis (karyotyping) when evaluating recurrent pregnancy loss to assess for balanced translocations.

When a pregnancy or child is diagnosed with a trisomy, families often seek information about the chance for recurrence in future pregnancies. Recurrence risk for a family depends on the underlying mechanism of the trisomy pregnancy. Most trisomies occur sporadically and have a relatively low recurrence risk. However, if a trisomy is caused by the inheritance of a parental balanced translocation, such as a Robertsonian translocation, the recurrence risk may be higher. A Robertsonian translocation is a type of balanced chromosome rearrangement in which two acrocentric chromosomes become fused together. Individuals who carry a balanced Robertsonian translocation typically have no health concerns but have an increased chance of producing eggs or sperm with extra or missing chromosomal material, which can result in a trisomy pregnancy.

Common pitfall: CMA can confirm the presence of an extra chromosome in a pregnancy or newborn, but it cannot distinguish whether the trisomy occurred as a random event or due to the inheritance of a parental balanced or Robertsonian translocation. CMA cannot detect balanced chromosome rearrangements, so a normal CMA result would not rule out a parent having a balanced or Robertsonian translocation.

Recommendation: If CMA detected a trisomy in the affected individual or pregnancy, follow up with a karyotype for the affected individual to assess for balanced translocations. Additionally, offering karyotypes to the affected individual’s parents could be considered.

Selecting the appropriate genetic test begins with clearly defining the clinical question and understanding the capabilities and limitations of the available cytogenetic tests, specifically chromosomal microarray (CMA). While CMA offers high-resolution detection of copy number changes (eg, microdeletions and microduplications), it cannot identify balanced chromosomal rearrangements (such as translocations) or small sequence-level variants associated with single-gene disorders. Therefore, relying solely on CMA in certain clinical scenarios may lead to incomplete or misleading results. Supplying relevant clinical information to the performing lab, including the reason for testing, and providing any relevant personal or family history also supports accurate testing and interpretation.

This information is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.