ArticleEuropean journal of human genetics : EJHG2023
Re-evaluation and re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 18.
Article in European journal of human genetics : EJHG, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 19 citations in OpenAlex.
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- Heterogeneity of monogenic epilepsy in loci, phenotypes, and treatment approaches.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- Case Report: Diagnostic odyssey in rare diseases: when genetic variants are misinterpreted.Frontiers in pediatrics · 2026Article
- Broadening the inheritedGenetics in medicine open · 2026Article
- Should recipient parents have access to gamete donors' raw genomic data? Clinical, legal, and ethical considerations.Journal of assisted reproduction and genetics · 2025Article
- Association of genetic variants, protein domains, and phenotypes in the ZMIZ1 syndromic neurodevelopmental disorder.Frontiers in neuroscience · 2025Article
- Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases.Orphanet journal of rare diseases · 2024Article
- 2023 in the European Journal of Human Genetics.European journal of human genetics : EJHG · 2024Article
- Molecular mechanisms of human overgrowth and use ofFrontiers in genetics · 2024Review
- Case report: Novel compound heterozygousFrontiers in immunology · 2024Article
- Expanding what we know about rare genetic diseases.European journal of human genetics : EJHG · 2023Article
- Re-evaluation and re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 18.European journal of human genetics : EJHG · 2023Article
- Unveiling the hidden: revisiting the potential of old genetic data for rare disease research.European journal of human genetics : EJHG · 2023Article
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4 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
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-analysis. In 28/152 (18%) families, we identified a clinically relevant change. Ten previously reported (likely) pathogenic variants were re-classified as VUS/benign. In one case, the GDA (TSEN15) validity was judged as limited, and in five cases GDAs are meanwhile established. We identified 12 new disease causing variants. Two previously reported variants were missed by our updated pipeline due to alignment or reference issues. Our results support the need to re-evaluate screening studies, not only the negative cases but including supposedly solved ones. This also applies in a diagnostic setting. We highlight that the complexity of computational re-analysis for old data should be weighed against the decreasing re-testing costs. Since extensive re-analysis per case is beyond the resources of most institutions, we recommend a screening procedure that would quickly identify the majority (83%) of new variants.
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