The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity.
Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized.
Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families.
We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.
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We thank the families for participating in this study. We thank Michio Hirano for kindly providing updated clinical information. R.v.d.L. was supported by a Rubicon fellowship from the Netherlands Organization for Scientific Research (NWO & ZONMW, 452172015).
S.R., C.D.C., and M.R.H. are employees of PerkinElmer Genomics, Inc., but were not involved in the testing of these families. The other authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Shen, J.J., Wortmann, S.B., de Boer, L. et al. The role of clinical response to treatment in determining pathogenicity of genomic variants. Genet Med (2020). https://doi.org/10.1038/s41436-020-00996-9
- 2015 ACMG/AMP guidelines
- treatable human conditions
- clinical genetic testing
- variant classification