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What are you missing? A review of the utility of characterization studies as part of chromosomal microarray analysis 

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Chromosomal microarray (CMA) testing is a key diagnostic tool in congenital genetics. For some copy number variations (CNVs), for example combinations of terminal deletions and duplications, an orthogonal follow-up technique—such as fluorescence in situ hybridization (FISH) or karyotype—may be useful to further investigate chromosome structure. This may inform the underlying genetic mechanisms and provide potential recurrence risks. However, this approach is not universally adopted across laboratories offering CMA testing. We aimed to evaluate the utility of follow-up studies as part of CMA testing in our laboratory, specifically to gain insight into chromosome structure, mechanisms, and recurrence risks.

 

Methods:
We conducted a retrospective review of all postnatal and products of conception (POCs) CMA cases reported in our laboratory from January 1 to October 31, 2024. We focused on cases in which FISH and/or karyotype were performed as follow-up strategies to structurally characterize abnormalities observed by CMA. Characterization studies are performed as part of CMA testing in the context of: acrocentric aneuploidies, terminal, pericentromeric and/or mosaic CNVs, or if a more complex rearrangement is suspected. We determined the percentage of cases that required characterization studies, identified the microarray findings prompting these follow-up tests, and evaluated whether additional structural or mechanistic information was gained.

 

Results:
In 2024 our laboratory reported 4582 CMA cases: 2,691 (59%) postnatal, and 1,891 (41%) POCs. Characterization studies were performed in 417 cases (9%), comprising 276 cases (6.4%) with karyotype, 132 cases (2.9%) with FISH, and 9 cases (0.2%) utilizing both techniques. Karyotype was most used in POCs (187 cases), while FISH was more commonly used in postnatal (89 cases). Most cases that employed both techniques were postnatal (6 cases).

Most cases requiring characterization studies involved autosomal trisomies of acrocentric chromosomes, which accounted for 251 cases (60.2%) of the 417, and approximately 75% were POCs. Deletions accounted for 70 cases (16.8%), duplications for 22 cases (5.3%) and there were 3 cases of triplications (0.7%). Unbalanced translocations or pericentric inversions were suspected in 40 cases (9.6%), abnormalities of ploidy in 5 cases (1.2%), tetrasomy in 2 cases (0.5%) and 13 cases (3.1%) with either rings, markers, isochromosomes or isodicentric chromosomes. Additionally, 4 cases (1.0%) involved sex chromosome aneuploidies, and 1 case (0.2%) was due to maternal cell contamination.

 

Follow-up studies confirmed the CNV findings in all but 13 cases, 9 of which were POCs. The most common reason for non-confirmation was maternal cell contamination. In 58 of the 417 cases (14%) (32 postnatals and 26 POCs) where characterization studies were performed, additional structural or mechanistic information was obtained, many of which had clinical implications for parental testing. In approximately 71% of these 58 cases, the result demonstrated a derivative of a translocation, inversion or an unbalanced translocation and 29% had either rings, markers, isochromosomes or isodicentric chromosomes. Notably, in 50 of these 58 cases, the CNV detected by microarray was not a trisomy. Thus, in all cases that were not autosomal trisomies for which characterization was performed, 30% benefited from additional relevant information.

 

Conclusion:
Our laboratory’s experience with orthogonal characterization studies in CMA testing demonstrates the utility of performing these studies as part of the CMA service, notably for CNVs that are suspicious for genomic rearrangements that often impact recurrence risk estimates. This aids in more informative interpretation of the CMA result, which can have positive impacts for patient care, and facilitate familial testing as needed to identify balanced rearrangements.  As NGS-based whole genome techniques are increasingly adopted, our data supports the clinical utility of performing characterization studies to inform structure and recurrence risks.

 

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