2023
DOI: 10.1038/s41431-023-01425-6
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Re-evaluation and re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 18%

Abstract: Iterative re-analysis of NGS results is not well investigated for published research cohorts of rare diseases. We revisited a cohort of 152 consanguineous families with developmental disorders (NDD) reported five years ago. We re-evaluated all reported variants according to diagnostic classification guidelines or our candidate gene scoring system (AutoCaSc) and systematically scored the validity of gene-disease associations (GDA). Sequencing data was re-processed using an up-to-date pipeline for case-level re-… Show more

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Cited by 10 publications
(4 citation statements)
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“…The importance of re-analysis extends beyond unsolved cases but also for cases previously considered resolved but with insufficient evidence. For instance, in a study of a follow-up cohort comprising 152 consanguineous families with developmental disorders, re-analysis of ES data after 5 years revealed 5 new gene-disease associations and led to the reclassification of 10 variants previously reported as pathogenic [29].…”
Section: Discussionmentioning
confidence: 99%
“…The importance of re-analysis extends beyond unsolved cases but also for cases previously considered resolved but with insufficient evidence. For instance, in a study of a follow-up cohort comprising 152 consanguineous families with developmental disorders, re-analysis of ES data after 5 years revealed 5 new gene-disease associations and led to the reclassification of 10 variants previously reported as pathogenic [29].…”
Section: Discussionmentioning
confidence: 99%
“…Re-analyses of apparently solved cases is also recommendable to identify over-classified variants and associations. A re-evaluation can be performed after certain time intervals (e.g., every 5 years as suggested by ( Bartolomaeus et al, 2023 )) but it is difficult to estimate what timeframes are adequate for which disease entity and if the re-analyses should be performed for all patients available, or only for those where certain levels of analysis have been performed already. In the light of the rapidly developing fields of omic techniques it is also worth considering if re-analyses should be performed with the old sequencing data sets or with new data generated by up-to-date techniques.…”
Section: Discussion/perspectivesmentioning
confidence: 99%
“…Second, the reanalysis strategy can implement additional sequencing, variant filtering or ancillary technologies to enhance the molecular diagnostic yield. ES-based resequencing with superior advancements in sequencing chemistry compared to outdated exome data can significantly upgrade data quality and is recommended by medical genetics guidelines (12,14,76,77). Moreover, the application of trio-ES has been shown to improve variant prioritization and interpretation, allowing for segregation and variant phasing in the affected proband and potentially affected family members (12,20,72,78,79).…”
Section: Discussionmentioning
confidence: 99%