While doing research on genes possibly involved in a specific phenotype, you can run in to several difficulties for the interpretation and classification of mutations found, consequently making predictions on causality hard. It is my aim to help you, so you can get an good idea of the pathogenicity of your mutation(s). Using several tools for interpretation I can assist you not only with an answer of the pathogenicity but also with attractive publication-ready figures.
Dear Rene Mulder!
Here is my answer. Please check it and make some comments!
Sincerely yours!
Dr. Bratko Filipič
Email: [email protected]
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Guidelines for implicating sequence variants in human disease
General guidelines
- Provide complete positive and negative evidence associated with the gene or variant implication, not just the results that are consistent with pathogenicity.
- In all cases in which it is possible, place genetic, informatic and experimental results within a quantitative framework: determine the probability of observing this result by chance with a randomly selected variant or gene.
- Take advantage of public data sets of genomic variation, functional genomic data and model-organism phenotypes.
- Do not regard prior reports of gene or variant implication as definitive: to the degree that supporting data are available, reassess them as rigorously as your own data.
- Describe and assess clearly the available evidence supporting prior reports of gene or variant implication.
Assessment of evidence for candidate disease genes
- In presumed monogenic-disease cases, evaluate genes previously implicated in similar phenotypes before exploring potential new genes.
- Report a new gene as confidently implicated only when variants in the same gene and similar clinical presentations have been confidently implicated in multiple unrelated individuals.
- In all cases in which it is possible, apply statistical methods to compare the distribution of variants in patients with large matched control cohorts or well-calibrated null models.
Assessment of evidence for candidate pathogenic variants
- Determine and report the formal statistical evidence for segregation or association of each variant, and its frequency in large control populations matched as closely as possible to patients in terms of ancestry.
- Recognize that strong evidence that a variant is deleterious (in an evolutionary sense) and/or damaging (to gene function) is not sufficient to implicate a variant as playing a causal role in disease.
- Predict variant deleteriousness with comparative genomic approaches, but avoid considering any single method as definitive or multiple methods as independent lines of evidence for implication.
- Validate experimentally the predicted damaging impact of candidate variants using assays of patient-derived tissue or well-established cell or animal models of gene function.
- Avoid assuming that implicated variants are fully penetrant, or completely explanatory in any specific disease case.
Publications and reporting
- Assess and report objectively the overall strength and cohesiveness of the evidence supporting pathogenicity for all variants listed in a publication.
- In all cases in which it is possible, ensure that the level of confidence of pathogenicity and supporting evidence are propagated in variant databases.
- Deposit genotype and phenotype data for both controls and disease patients, and for resultant analyses demonstrating associations, in publicly accessible databases, to the maximum degree permissible under study-specific participant consent and ethical approval.
- If returning results for clinical use, highlight strong, actionable findings but also ensure that uncertain or ambiguous findings are clearly conveyed as such, along with appropriate supporting evidence.
- Provide clear cautions regarding decision-making based on variants with limited evidence when the potential for use in medical interventions is high.
Dear Filipic,
Thank you very much for outlining all of the above. This again makes it ever so clear how difficult a correct interpretation and classification of gene mutations is. My intensions aren't to give a difinitive answer to if a mutation is pathogenic or not. In stead, I will assist in providing an answer to this question. Your outlines are very valuable in this case. I would be happy to dive into your guidelines a bit more and perhaps contribute in adding some of my knowledge/experiences. Could you perhaps send a copy?
Best,
René
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