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On the probability that a novel variant is a disease-causing mutation.

Mitchell AA et al.

Genome Research. 2005 Jul; 15(7):960-966

https://doi.org/10.1101/gr.3761405PMID:15965029

When a novel variant is found in a patient and not in a group of controls, it becomes a candidate for the disease-causing mutation in that patient. At present, no sampling theory exists for assessing the probability that the novel SNP might actually be a neutral variant. We have developed a population genetics-based method for calculating a P-value for a mutation-detection effort. Our method can be applied to a heterozygous patient, a homozygous patient, with or without inbreeding, or to a patient who is a compound heterozygote. Additionally, the method can be used to calculate the probability of finding a neutral variant at frequencies that differ between a group of patients and a group of controls, given some length of sequence examined. This method accounts for the multiple testing that is inherent in identification of variants through sequencing, to be used in subsequent case-control analyses. We show, for example, that for complete resequencing of 10 kb, the probability of finding a neutral variant in a patient and not in 50 controls is about 15%. Thus, discovery of a variant in a patient and not in a group of controls is, on its own, very weak evidence of involvement with disease.

Mitchell AA¹,
Chakravarti A ,
Cutler DJ

Affiliations

¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA

This work was supported by:

NHGRI NIH HHS, United States
GrantID: HG2757-1

NHGRI NIH HHS, United States
GrantID: U54 HG002757

Classifications

Technical Advance

Evaluations

The authors make an important technical contribution by providing a probabilistic framework to quantify the likelihood that a variant is neutral not just at one locus, but for an entire sequence.Most evaluations of the clinical significance of a new variant depend on the gestalt of experts and all too often these impressions are not subsequently borne out.This problem is growing with the large amount of sequence obtained without a specific clinical rationale. This paper provides a solid mathematical basis for a limited number of scenarios (of transmission and recombination) such that if the assumptions of those scenarios hold, the probabilities that the variants cause a change in phenotype can be calculated. Unfortunately, this important work is not generally applicable but does help to provide a set of bounds on the likelihood of the clinical significance. More work in this area will be essential for the translational impact of current and future sequencing efforts.

This paper presents a population genetics approach for the calculation of a P-value for the purpose of evaluating DNA variants for possible pathogenicity.In current practice, the selection of the number of control samples to be used in mutation screening projects is determined arbitrarily.This manuscript provides guidance towards selecting a sufficient number of control samples to provide statistical significance of putative disease-causing mutations. The methodology can be applied to dominant or recessive disease models as well as evaluating variants for which allele frequencies are found to differ between a group of patients and controls.

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Bioinformatics, Biomedical Informatics & Computational Biology
Genomics |Sequence Analysis
Biotechnology
Genomics |Medical Genetics
Genomics & Genetics
Genomics |Medical Genetics |Molecular Systems Medicine |Sequence Analysis
Molecular Medicine
Medical Genetics |Molecular Systems Medicine
Physiology
Molecular Systems Medicine