doi: 10.1101/gr.3761405. Epub 2005 Jun 17.
On the probability that a novel variant is a disease-causing mutation
Affiliations
- PMID:15965029
- PMCID: PMC1172040
- DOI: 10.1101/gr.3761405
Item in Clipboard
On the probability that a novel variant is a disease-causing mutation
Adele A Mitchell et al. Genome Res.2005 Jul.
Display options
Format
Display options
Format
Abstract
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.
Similar articles
- Development of a diagnostic genetic test for simplex and autosomal recessive retinitis pigmentosa.Clark GR, Crowe P, Muszynska D, O'Prey D, O'Neill J, Alexander S, Willoughby CE, McKay GJ, Silvestri G, Simpson DA.Clark GR, et al.Ophthalmology. 2010 Nov;117(11):2169-77.e3. doi: 10.1016/j.ophtha.2010.02.029. Epub 2010 Jun 29.Ophthalmology. 2010.PMID:20591486
- A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: a cohort allelic sums test (CAST).Morgenthaler S, Thilly WG.Morgenthaler S, et al.Mutat Res. 2007 Feb 3;615(1-2):28-56. doi: 10.1016/j.mrfmmm.2006.09.003. Epub 2006 Nov 13.Mutat Res. 2007.PMID:17101154
- Mutational screening of CYP1B1 in Turkish PCG families and functional analyses of newly detected mutations.Bagiyeva S, Marfany G, Gonzalez-Angulo O, Gonzalez-Duarte R.Bagiyeva S, et al.Mol Vis. 2007 Aug 27;13:1458-68.Mol Vis. 2007.PMID:17893647
- Variants in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.Shimizu M, Kobayashi Y, Hayashi S, Aoki Y, Yamazaki H.Shimizu M, et al.Mol Genet Metab. 2012 Nov;107(3):330-4. doi: 10.1016/j.ymgme.2012.06.014. Epub 2012 Jul 1.Mol Genet Metab. 2012.PMID:22819296
- [Disease-causing mutations versus neutral polymorphism: use of bioinformatics and DNA diagnosis].Machácková E.Machácková E.Cas Lek Cesk. 2003 Mar;142(3):150-3.Cas Lek Cesk. 2003.PMID:12756842Review.Czech.
Cited by
- How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases?Kochański A.Kochański A.J Appl Genet. 2006;47(3):255-60. doi: 10.1007/BF03194633.J Appl Genet. 2006.PMID:16877806Review.
- Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3.Verma R, Holmans P, Knowles JA, Grover D, Evgrafov OV, Crowe RR, Scheftner WA, Weissman MM, DePaulo JR Jr, Potash JB, Levinson DF.Verma R, et al.Biol Psychiatry. 2008 Jun 15;63(12):1185-9. doi: 10.1016/j.biopsych.2008.02.005. Epub 2008 Mar 25.Biol Psychiatry. 2008.PMID:18367154Free PMC article.
- A new chromosome x exon-specific microarray platform for screening of patients with X-linked disorders.Bashiardes S, Kousoulidou L, van Bokhoven H, Ropers HH, Chelly J, Moraine C, de Brouwer AP, Van Esch H, Froyen G, Patsalis PC.Bashiardes S, et al.J Mol Diagn. 2009 Nov;11(6):562-8. doi: 10.2353/jmoldx.2009.090086. Epub 2009 Sep 24.J Mol Diagn. 2009.PMID:19779134Free PMC article.
- Genetic evidence and integration of various data sources for classifying uncertain variants into a single model.Goldgar DE, Easton DF, Byrnes GB, Spurdle AB, Iversen ES, Greenblatt MS; IARC Unclassified Genetic Variants Working Group.Goldgar DE, et al.Hum Mutat. 2008 Nov;29(11):1265-72. doi: 10.1002/humu.20897.Hum Mutat. 2008.PMID:18951437Free PMC article.
- Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.Sosnay PR, et al.Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.Nat Genet. 2013.PMID:23974870Free PMC article.
References
- Colomb, E., Kaplan, J., and Garchon, H.J. 2003. Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France. Hum. Mutat. 22: 496. - PubMed
- DiFonzo, A., Bordoni, A., Crimi, M., Galbiati, S., DelBo, R., Bresolin, N., and Comi, G.P. 2003. POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum. Mutat. 22: 498-499. - PubMed
- Eng, B., Nakamura, L.N., O'Reilly, N., Schokman, N., Nowaczyk, M.M., Krivit, W., and Waye, J.S. 2003. Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). Hum. Mutat. 22: 418-419. - PubMed
- Ewens, W.J. 1974. A note on the sampling theory for infinite alleles and infinite sites models. Theor. Popul. Biol. 6: 143-148. - PubMed
Web site references
- http://www.hugo-international.org; The Human Genome Organization (HUGO).
- http://www.ncbi.nlm.nih.gov/omim/; Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University and National Center for Biotechnology Information, National Library of Medicine, 2000.
Publication types
MeSH terms
Related information
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources