Abstract
BackgroundVariants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as secondary findings. Secondary findings are not the primary targets of whole exome and genome sequencing (WES/WGS) assay but can be of great practical value in early disease prevention and intervention. The driving force for this study was to investigate the impact of racial difference and disease background on secondary findings. Here, we analyzed secondary findings frequencies in 421 whole exome-sequenced Chinese children who are phenotypically normal or bear congenital heart diseases/juvenile obesity. In total, 421 WES datasets were processed for potential deleterious variant screening. A reference gene list was defined according to the American College of Medical Genetics and Genomics (ACMG) recommendations for reporting secondary findings v2.0 (ACMG SF v2.0). The variant classification was performed according to the evidence-based guidelines recommended by the joint consensus of the ACMG and the Association for Molecular Pathology (AMP).ResultsAmong the 421 WES datasets, we identified 11 known/expected pathogenic variants in 12 individuals, accounting for 2.85% of our samples, which is much higher than the reported frequency in a Caucasian population. In conclusion, secondary findings are not so rare in Chinese children, which means that we should pay more attention to the clinical interpretation of sequencing results.
Highlights
During whole exome and whole genome sequencing (WES/WGS) data interpretation, variants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as incidental findings or secondary findings
Since the American College of Medical Genetics and Genomics first published recommendations for reporting clinical exome and genome sequencing secondary findings [1], close attention has been paid to the incidence and clinical significance of secondary findings [2,3,4,5,6,7]
These results indicate that the pathogenicity of other distinct non-protein-truncating mutations (PTMs) variants in our sample might be overrated by these databases, which suggests the need to be cautious when using these databases to perform clinical data interpretation
Summary
During whole exome and whole genome sequencing (WES/WGS) data interpretation, variants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as incidental findings or secondary findings. These mutated genes are not first-tier targets of the test but indicate a high risk of certain medically actionable diseases. Variants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as secondary findings. Secondary findings are not the primary targets of whole exome and genome sequencing (WES/WGS) assay but can be of great practical value in early disease prevention and intervention. The variant classification was performed according to the evidence-based guidelines recommended by the joint consensus of the ACMG and the Association for Molecular Pathology (AMP)
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