Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Kim, So Young; Lee, Seungmin; Seo, Go Hun; Kim, Bong Jik; Oh, Doo Yi; Han, Jin Hee; Park, Moo Kyun; Lee, So Min; Kim, Bong Gi; Yi, Nayoung; Kim, Namju Justin; Koh, Doo Hyun; Hwang, Sohyun; Keum, Changwon; Choi, Byung Yoon

doi:10.1038/s41598-021-99007-3

Cited by 2 publications

(1 citation statement)

References 57 publications

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“…However, in a clinical setting, trio testing would not be feasible due to the increased costs of parental WES and the possibility that parental DNA is not available. In addition, the curating times and costs of WES analysis were reduced due to automatic variant interpretation by EVIDENCE (Seo et al 2020 ; Kim et al 2021 ), thus suggesting that proband-only WES by EVIDENCE is a comparable diagnostic approach for these patients in a routine clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Seo¹,

Lee²,

Lee³

et al. 2022

Mol Med

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Background The diagnostic yield of whole-exome sequencing (WES) varies from 30%–50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10–15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses. Methods The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems. Results At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period. Conclusion Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.

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Section: Discussionmentioning

confidence: 99%

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Seo¹,

Lee²,

Lee³

et al. 2022

Mol Med

Self Cite

View full text Add to dashboard Cite

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Improving genetic diagnosis by disease-specific, ACMG/AMP variant interpretation guidelines for hearing loss

Kim

et al. 2022

Sci Rep

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The 2018 Hearing Loss Expert Panel (HL-EP)-specific guidelines specified from the universal 2015 ACMG/AMP guidelines are proposed to be used in genetic HL, which prompted this study. A genetic HL cohort comprising 135 unrelated probands with available exome sequencing data was established. Overall, 169 variants were prioritized as candidates and interpreted using the 2015 ACMG/AMP and 2018 HL-EP guidelines. Changes in rule application and variant classification between the guidelines were compared. The concordance rate of variant classification of each variant between the guidelines was 71.60%, with significant difference. The proportion of pathogenic variants increased from 13.02% (2015) to 29.59% (2018). Variant classifications of autosomal recessive (AR) variants that previously belonged to VUS or likely pathogenic in the 2015 guidelines were changed toward pathogenic in the 2018 guidelines more frequently than those of autosomal dominant variants (29.17% vs. 6.38%, P = 0.005). Stratification of the PM3 and PP1 rules in the 2018 guidelines led to more substantial escalation than that in the 2015 guidelines. We compared the disease-specific guidelines (2018) with the universal guidelines (2015) using real-world data. Owing to the sophistication of case-level data, the HL-specific guidelines have more explicitly classified AR variants toward “likely pathogenic” or “pathogenic”, serving as potential references for other recessive genetic diseases.

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Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Cited by 2 publications

References 57 publications

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

Improving genetic diagnosis by disease-specific, ACMG/AMP variant interpretation guidelines for hearing loss

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