Abstract
Exome sequencing has become an effective diagnostic method for Mendelian disorders. But the quality of services differs widely across laboratories in China, particularly in variant classification, even with the adoption of the ACMG guidelines. As an effort of quality control and improvement for better clinical utilization of exome sequencing, we assessed the exome data analysis and clinical reporting among Chinese laboratories. Five raw datasets of real clinical samples with associated phenotypes were sent to 53 laboratories. The participants independently performed secondary analysis, variant classification, and reporting. The first round of results was used for identifying problems associated with these aspects. Subsequently, we implemented several corrective actions and a training program was designed based on the identified issues. A second round of five datasets were sent to the same participants. We compared the performances in variant interpretation and reporting. A total of 85.7% (42/49) of participants correctly identified all the variants related with phenotype. Many lines of evidence using the ACMG guidelines were incorrectly utilized, which resulted in a large inter-laboratory discrepancy. After training, the evidence usage problems significantly improved, leading to a more consistent outcome. Participants improved their exome data analysis and clinical reporting capability. Targeted training and a deeper understanding of the ACMG guidelines helped to improve the clinical exome sequencing service in terms of consistency and accuracy in variant classification in China.
Highlights
Exome sequencing has proven to be an effective strategy for gene discovery and clinical diagnosis for patients with Mendelian disorders, which herald a new era of genomic medicine (Yang et al, 2013, 2014; Lee et al, 2014; Retterer et al, 2016; Wright et al, 2018)
Many issues have been reported regarding the inconsistency of variant calling, variant annotation, variant filtration, variant classification, and variant reporting in clinical diagnostic settings
In addition to common issues, China is confronted with unique challenges: (1) a lack of professional, clinical, and medical geneticists, the equivalent of ABMGG-certified medical geneticists in the United States; (2) a lack of genetic counselors who play important roles in collecting/delineating clinical information, variant classification, report drafting, and genetic counseling for both physicians and patients; and (3) a lack of regulations like the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88) in the United States
Summary
Exome sequencing has proven to be an effective strategy for gene discovery and clinical diagnosis for patients with Mendelian disorders, which herald a new era of genomic medicine (Yang et al, 2013, 2014; Lee et al, 2014; Retterer et al, 2016; Wright et al, 2018). In addition to common issues, China is confronted with unique challenges: (1) a lack of professional, clinical, and medical geneticists, the equivalent of ABMGG-certified medical geneticists in the United States; (2) a lack of genetic counselors who play important roles in collecting/delineating clinical information, variant classification, report drafting, and genetic counseling for both physicians and patients; and (3) a lack of regulations like the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88) in the United States With these challenges in mind, the National Center of Clinical Laboratories (NCCLs) organized an initial assessment focusing on exome variant analysis and clinical reporting in China, as part of the effort to assess the performances of Chinese laboratories offering clinical diagnostic tests using exome. NCCLs conducted a training program after the first survey and educated the laboratories on how to apply ACMGAMP criteria correctly and move toward more consistent variant interpretations
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