DISCRIMINATOR: Assigning Cohort-Wide Provisional Pathogenicity Classifications to CNVs

Abstract

The interpretation of clinical chromosomal microarrays (CMAs) has historically relied on the relevance of identified copy number variants (CNVs) to the clinical phenotype. New interpretation guidelines are focused on standardizing pathogenicity classifications based on genomic location, gene content, and previous publications, rather than the immediate clinical relevance. Here we report on DISCRIMINATOR, which was developed to assign provisional pathogenicity classifications based on genomic location by integrating information on putative benign and pathogenic loci in the human genome. However, its application extends beyond that of a simple classifier. The novel utility of DISCRIMINATOR is its ability to operate on a cohort-level and easily integrate updated definitions of benign and pathogenic regions of the human genome. We used DISCRIMINATOR to assign provisional pathogenicity classifications ('Benign', 'Secondary', 'Primary' or 'Non-Coding') to 87,808 CNVs in 3,362 cases ascertained through clinical CMA testing. The majority of identified CNVs were provisionally classified as 'Benign' or 'Non-Coding' and consistent with their prevalence rates, 15q11.2, 16p11.2, and 22q11.2 were the most common 'Primary' CNVs detected. Targeted re-analysis led to the identification of several cases where DISCRIMINATOR identified a 'Primary' CNV within a case that had a non-Abnormal CMA test result, and several cases where only benign and/or non-coding CNVs were identified in reports with a 'VUS' CMA test result. Together these results show the utility of large-scale re-analysis of CMA data and how DISCRIMINATOR addresses this long-standing challenge.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by R01DE021071 (MP and JM), the Stead Family Department of Pediatrics (AW, HM, BD) and the Interdisciplinary Genetics T32 Predoctoral Training Grant (T32 GM 008629; AW).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of the University of Iowa has determined that this work does not meet the regulatory definition of human subjects research and does not require review.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

DISCRIMINATOR is publicly available on GitHub at https://github.com/aswetzel/DISCRIMINATOR. All non-case data produced and analyzed in the present study are included in this published article and its supplementary information. Case data is available upon reasonable request to the authors.

https://github.com/aswetzel/DISCRIMINATOR

留言 (0)

沒有登入
gif