ArticleGenome medicine2023
Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss.
Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Telomere length analysis using qPCR in aplastic anemia: prevalence and predictive value for germline mutation status.Blood research · 2026Article
- From enrichment to interpretation: PS4-driven reclassification in Taiwanese inherited retinal degeneration.Human genomics · 2026Article
- GDC: Integration of Multi-Omic and Phenotypic Resources to Unravel the Genetic Pathogenesis of Hearing Loss.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Enhanced identification of novel pathogenic variants in hereditary hearing loss through physical phasing with integrated short and long-read sequencing data.Molecular genetics and genomics : MGG · 2025Article
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14 authors.
Funding
Abstract
backgroundThe American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case-control cohorts is lacking.
methodsTo address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets.
resultsIn subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF < 0.0005, and subset 3, comprising variants found only in cases and absent from controls, we defined the PS4_Supporting threshold (OR > 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients.
conclusionsOur study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.
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