How Do I Confirm that a New Mutation is Pathogenic?

Abstract

Whole exome, genome sequencing, and other massive parallel next generation sequencing technologies have increasingly been used as a clinical diagnostic tool in recent years. Although sequencing technologies are becoming more affordable and widely used, the interpretation of variants from these large datasets at the level of personalized medicine is not clear‐cut. For example, many rare missense variants identified may or may not have an impact on gene function and can be problematic to interpret in a clinical setting. Thus, there is a need for a systematic approach to applying, reporting, and evaluating variants identified. One important aspect is to determine the pathogenicity of a variant based on scientific literature. This tutorial is meant to serve as an introduction to scoring pathogenicity of variants, enabling movement disorder specialists to familiarize themselves with online tools to independently determine pathogenicity of variants identified in genetic testing reports.

View Supplementary Video 1

Author Roles

Joanne Trinh: working out concept, script writing; Vera Tadic: working out concept, script writing; Christine Klein: idea for the video, working out concept, video editing, critical supervision.

Disclosures

Ethical Compliance Statement: Approval by an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding sources and conflicts of interest: Christine Klein is the recipient of a career development award from the Hermann and Lilly Schilling Foundation and is funded by the DFG (FOR2488). Joanne Trinh holds an Alexander von Humboldt Fellowship a CIHR Fellowship and an Add‐on fellowship from the Joachim Herz Foundation. MDSGene is sponsored by the International Parkinson and Movement Disorder Society.

Financial Disclosures for previous 12 months: All authors are employed by the University of Luebeck. Joanne Trinh received grants from Alexander von Humboldt Fellowship, CIHR Fellowship, and the Joachim Herz Stiftung Add‐on fellowship. Christine Klein reports the following disclosures: she is a medical advisor to Centogene and Biogen; she received honoraria from the Wellcome Trust Review Board and the Scientific Advisory Board of the Else Kroener Fresenius Foundation; she received grants from Movement Disorder Society, the German Research Foundation, the BMBF, European Community, and intramural funds from the University of Luebeck; she also receives royalties from Oxford University Press.

Supporting information

A video accompanying this article is available in the supporting information here.

Video S1. How do I confirm that a new mutation is pathogenic?

Script S1. Transcript of Video S1 narration.