Copy-number variants in the ACMG secondary finding genes: A reporting framework for clinical cytogeneticists

Mahmoud Aarabi; Helia Darabi; Aryan Bashar; Daniel Bellissimo; Aleksandar Rajkovic; Svetlana A Yatsenko

doi:10.1016/j.gimo.2024.101839

Copy-number variants in the ACMG secondary finding genes: A reporting framework for clinical cytogeneticists

Genet Med Open. 2024 Mar 13:2:101839. doi: 10.1016/j.gimo.2024.101839. eCollection 2024.

Authors

Mahmoud Aarabi^{1

2}, Helia Darabi², Aryan Bashar³, Daniel Bellissimo², Aleksandar Rajkovic^{4

5}, Svetlana A Yatsenko^{1

2

6}

Affiliations

¹ Departments of Pathology, and Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
² Medical Genetics and Genomics Laboratories, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA.
³ Data Science Graduate Program, University of Colorado Boulder, Boulder, CO.
⁴ Department of Pathology, and Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA.
⁵ Institute of Human Genetics, University of California San Francisco, San Francisco, CA.
⁶ Magee-Womens Research Institute, Pittsburgh, PA.

Abstract

Purpose: To determine the pathogenicity and frequency of copy-number variants (CNV) in the 81 secondary finding (SFv3.2) genes recommended by the American College of Medical Genetics and Genomics (ACMG).

Methods: Review of published evidence on pathogenicity of partial or complete copy-number losses or gains in ACMG SFv3.2 was performed. Frequency of reportable CNVs in the ACMG SFv3.2 genes was investigated among 10,959 patients tested by chromosomal microarray analysis in a single academic testing laboratory at the University of Pittsburgh Medical Center during 2011 to 2023.

Results: We identified 58 ACMG SFv3.2 genes for which sufficient evidence supports reporting of partial or complete copy-number losses as secondary findings. On the contrary, reporting of copy-number gains was not supported by evidence in any of the ACMG SFv3.2 genes. Overall, CNVs in SFv3.2 genes were detected in 32 of 10,959 (0.29% or 1 in 343) patients in our cohort.

Conclusion: This study provides a framework for consistent reporting of CNVs, detected by chromosomal microarray analysis, exome, or genome sequencing, in any of the ACMG SFv3.2 genes. To our knowledge, this is the largest cohort of patients studied for estimation of frequency of reportable CNVs in the ACMG SFv3.2 genes.

Keywords: ACMG; Chromosomal microarray analysis (CMA); Copy-number variants (CNV); Cytogenetics; Secondary findings.