Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants

Abstract

The American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) recently published important new guidelines aiming to improve and standardize the pathogenicity classification of genomic variants. The Clinical Sequencing Exploratory Research (CSER) consortium evaluated the use of these guidelines across nine laboratories. One identified obstacle to consistent usage of the ACMG-AMP guidelines is the lack of a definition of cosegregation as criteria for pathogenicity classification. Cosegregation data differ from many other types of pathogenicity data in being quantitative. However, the ACMG-AMP guidelines do not define quantitative criteria for use of these data. Here, such quantitative criteria, in an easily implementable form, are proposed.

Figure 1

ACMG-AMP Pathogenicity Classification Guidelines Updated to Include Cosegregation The summary table of evidence categories and levels from the ACMG-AMP pathogenicity classification guideline paper by Richards et al. is shown and is updated to include the proposed cosegregation thresholds as outlined in Table 1. The strongest evidence level supported by a given N is selected. Figure adapted with permission from Richards et al.

Figure 2

Examples of Computation of Cosegregation Evidence These examples demonstrate the computation of N proposed here and contrast it to BF as computed by Bayrak-Toydemir et al., considering pedigrees from their paper. Filled-in pedigree members are affected, and hashed are highly suspicious for the phenotype. A positive sign indicates that the individual harbors the variant of interest, and a negative sign indicates that the individual was genotyped and does not harbor the variant of interest. The proband is identified with an arrow. Pedigrees reprinted with permission from Bayrak-Toydemir et al.