Limited diagnostic impact of duplications <1 Mb of uncertain clinical significance: a 10-year retrospective analysis of reporting practices at the Mayo Clinic

Abstract

Purpose

Copy-number variants (CNVs) of uncertain clinical significance are routinely reported in a clinical setting only when exceeding predetermined reporting thresholds, typically based on CNV size. Given that very few genes are associated with triplosensitive phenotypes, it is not surprising that many interstitial duplications <1 Mb are found to be inherited and anticipated to be of limited or no clinical significance.

Methods

In an effort to further refine our reporting criteria to maximize diagnostic yield while minimizing the return of uncertain variants, we performed a retrospective analysis of all clinical microarray cases reported in a 10-year window. A total of 1112 reported duplications had parental follow-up, and these were compared by size, RefSeq gene content, and inheritance pattern. De novo origin was used as a rough proxy for pathogenicity.

Results

Approximately 6% of duplications 500 kb–1 Mb were de novo observations, compared with approximately 14% for 1–2 Mb duplications (p = 0.0005). On average, de novo duplications had higher gene counts than inherited duplications.

Conclusion

Our data reveal limited diagnostic utility for duplications of uncertain significance <1 Mb. Considerations for revised reporting criteria are discussed and are applicable to CNVs detected by any genome-wide exploratory methodology, including exome/genome sequencing.

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Fig. 1: Size distribution of de novo duplications and RefSeq gene content assessment.

References

  1. 1.

    Schwartz S. Clinical utility of single nucleotide polymorphism arrays. Clin Lab Med. 2011;31:581–594.

    Article  Google Scholar 

  2. 2.

    Kearney HM, South ST, Wolff DJ, et al. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genet Med. 2011;13:676–679.

    Article  Google Scholar 

  3. 3.

    Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764.

    CAS  Article  Google Scholar 

  4. 4.

    Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742–745.

    CAS  Article  Google Scholar 

  5. 5.

    Stavropoulos DJ, Merico D, Jobling R, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012.

    CAS  Article  Google Scholar 

  6. 6.

    Shaffer LG, Beaudet AL, Brothman AR, et al. Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 2007;9:654–662.

    Article  Google Scholar 

  7. 7.

    South ST, Lee C, Lamb AN, et al. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 2013;15:901–909.

    CAS  Article  Google Scholar 

  8. 8.

    Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245–257.

    Article  Google Scholar 

  9. 9.

    Kang SH, Shaw C, Ou Z, et al. Insertional translocation detected using FISH confirmation of array-comparative genomic hybridization (aCGH) results. Am J Med Genet A. 2010;152A:1111–1126.

    Article  Google Scholar 

  10. 10.

    Neill NJ, Ballif BC, Lamb AN, et al. Recurrence, submicroscopic complexity, and potential clinical relevance of copy gains detected by array CGH that are shown to be unbalanced insertions by FISH. Genome Res. 2011;21:535–544.

    CAS  Article  Google Scholar 

  11. 11.

    Zepeda-Mendoza CJ, Ibn-Salem J, Kammin T, et al. Computational prediction of position effects of apparently balanced human chromosomal rearrangements. Am J Hum Genet. 2017;101:206–217.

    CAS  Article  Google Scholar 

  12. 12.

    Clinical Genome Resource (ClinGen). https://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml. Accessed March 2020.

  13. 13.

    MacDonald JR, Ziman R, Yuen RK, et al. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42:D986–992.

    CAS  Article  Google Scholar 

  14. 14.

    Newman S, Hermetz KE, Weckselblatt B, et al. Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. Am J Hum Genet. 2015;96:208–220.

    CAS  Article  Google Scholar 

  15. 15.

    Kearney HM, Thorland EC, Brown KK, et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–685.

    Article  Google Scholar 

  16. 16.

    Riggs ER, Church DM, Hanson K, et al. Towards an evidence-based process for the clinical interpretation of copy number variation. Clin Genet. 2012;81:403–412.

    CAS  Article  Google Scholar 

  17. 17.

    Itsara A, Wu H, Smith JD, et al. De novo rates and selection of large copy number variation. Genome Res. 2010;20:1469–1481.

    CAS  Article  Google Scholar 

  18. 18.

    Brock DJ, Shrimpton AE. Non-paternity and prenatal genetic screening. Lancet. 1991;338:1151.

    CAS  Article  Google Scholar 

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Correspondence to Cherisse A. Marcou PhD.

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Marcou, C.A., Pitel, B., Hagen, C.E. et al. Limited diagnostic impact of duplications <1 Mb of uncertain clinical significance: a 10-year retrospective analysis of reporting practices at the Mayo Clinic. Genet Med (2020). https://doi.org/10.1038/s41436-020-0932-0

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Keywords

  • copy-number variant
  • reporting criteria
  • duplication
  • triplosensitivity
  • microarray

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