April 18, 2018 –
At the annual American College of Medical Genetics (ACMG) meeting, Yi Huang, PhD, senior scientist and team leader for clinical analysis for medical/whole exome sequencing, presented on her lab’s experience with over 10,000 cases carried out from 2016-2017. Their results are one more sign that genomics in China is keeping up with the best facilities in the world.
WuXi NextCODE’s Shanghai facility has taken a critical step forward by implementing highly regarded standards for interpreting Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) results. Last week, at the annual American College of Medical Genetics (ACMG) meeting, Yi Huang, PhD, senior scientist and team leader for clinical analysis for medical/whole exome sequencing, presented on her lab’s experience with over 10,000 cases carried out from 2016-2017. Their results are one more sign that genomics in China is keeping up with the best facilities in the world.
Next Generation Sequencing (NGS) has grown rapidly in China over the last few years, adding substantially to both genomic data and understanding of the clinical implications of different variations. The WuXi NextCODE team carries out NGS testing for undiagnosed pediatric and adult patients, carrier testing for pre-pregnancy counseling and wellness-related screening. But determining which genetic variants are pathological is still one of the most complex tasks in clinical genetics. Many variants of unknown significance (VUSs) still arise, and some variants occur at very different rates in different populations. Labs also differ in how they classify genetic variations, leading to inconsistencies that slow diagnosis and medical research progress.
Most US-based labs now use the standards for variant interpretation developed by the ACMG and Association for Molecular Pathology (AMP). This has helped to reduce inconsistencies between lab findings and makes genomic test results more useful overall.
In her presentation, Huang described how WuXi NextCODE in Shanghai implemented ACMG/AMP standards and guidelines in their variant interpretation process. The five-tiered categorization system recommended by these guidelines includes pathogenic (P), likely pathogenic (LP), VUSs, likely benign (LB) and benign (B).
One of the challenges her lab faces is that many variants’ more common to Asian people have not yet been described in publications. To help address this issue, her team suggested adding two additional categories, VUS-LP (VUS but more toward to LP) and VUS-LB (VUS but more toward to LB), creating a seven-category system. Adding additional categories of VUSs, Huang explained, is not inconsistent with the ACMG guidelines. The goal was to help physicians more easily determine potentially pathogenic VUSs – making it more likely that patients who need further testing, counseling or other follow up receive it. Physicians, she pointed out, are more likely to ignore VUSs if they don’t get additional information about the risk they pose. In some cases, additional sequencing studies and an analysis of family history can determine that a VUS-LP is actually LP.
The group has taken other steps, including creating a modified ACMG-AMP interpretation protocol that combines assessments on both gene and variant levels. This is aimed at better flagging genes that have reduced penetrance, variable expressiveness, and/or lead to a wide range of age of disease onset. Moreover, the group has also adapted a more flexible weighting system. For example, they apply more weight to phenotypically-related recurrent de novo missense mutations. Finally, for ACMG recommended secondary findings, the group also introduced an expansion variant type to include Malignant Hyperthermia related VUS, aimed at identifying unrecognized but potentially harmful events.
Huang described several clinical cases and circumstances in China that support the need for the adjustments they’ve made to the guidelines. Overall, the WuXi NextCODE group have been able to create a robust variant interpretation system using the ACMG-AMP standards, with modifications that fit the particular needs of local communities.