Estimation of the incidence of a rare genetic disease through a two-tier mutation survey.
Abstract
Recent attempts to detect mutations involving single base changes or small deletions that are specific to genetic diseases provide an opportunity to develop a two-tier mutation-screening program through which incidence of rare genetic disorders and gene carriers may be precisely estimated. A two-tier survey consists of mutation screening in a sample of patients with specific genetic disorders and in a second sample of newborns from the same population in which mutation frequency is evaluated. We provide the statistical basis for evaluating the incidence of affected and gene carriers in such two-tier mutation-screening surveys, from which the precision of the estimates is derived. Sample-size requirements of such two-tier mutation-screening surveys are evaluated. Considering examples of cystic fibrosis (CF) and medium-chain acyl-CoA dehydrogenase deficiency (MCAD), the two most frequent autosomal recessive disease in Caucasian populations and the two most frequent mutations (delta F508 and G985) that occur on these disease allele-bearing chromosomes, we show that, with 50-100 patients and a 20-fold larger sample of newborns screened for these mutations, the incidence of such diseases and their gene carriers in a population may be quite reliably estimated. The theory developed here is also applicable to rare autosomal dominant diseases for which disease-specific mutations are found.
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- Allan JL, Phelan PD. Incidence of cystic fibrosis in ethnic Italians and Greeks and in Australians of predominantly British origin. Acta Paediatr Scand. 1985 Mar;74(2):286–289. [PubMed] [Google Scholar]
- Bennett MJ, Worthy E, Pollitt RJ. The incidence and presentation of dicarboxylic aciduria. J Inherit Metab Dis. 1987;10(3):241–242. [PubMed] [Google Scholar]
- De Braekeleer M, Daigneault J. Spatial distribution of the DF508 mutation in cystic fibrosis: a review. Hum Biol. 1992 Apr;64(2):167–174. [PubMed] [Google Scholar]
- Chakraborty R, Srinivasan MR, Daiger SP. Evaluation of standard error and confidence interval of estimated multilocus genotype probabilities, and their implications in DNA forensics. Am J Hum Genet. 1993 Jan;52(1):60–70. [PMC free article] [PubMed] [Google Scholar]
- Ferrie RM, Schwarz MJ, Robertson NH, Vaudin S, Super M, Malone G, Little S. Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene. Am J Hum Genet. 1992 Aug;51(2):251–262. [PMC free article] [PubMed] [Google Scholar]
- Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. [PubMed] [Google Scholar]
- Kølvraa S, Gregersen N, Blakemore AI, Schneidermann AK, Winter V, Andresen BS, Curtis D, Engel PC, Pricille D, Rhead W, et al. The most common mutation causing medium-chain acyl-CoA dehydrogenase deficiency is strongly associated with a particular haplotype in the region of the gene. Hum Genet. 1991 Aug;87(4):425–428. [PubMed] [Google Scholar]
- Lemna WK, Feldman GL, Kerem B, Fernbach SD, Zevkovich EP, O'Brien WE, Riordan JR, Collins FS, Tsui LC, Beaudet AL. Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. N Engl J Med. 1990 Feb 1;322(5):291–296. [PubMed] [Google Scholar]
- Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, Smith JC, Markham AF. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989 Apr 11;17(7):2503–2516. [PMC free article] [PubMed] [Google Scholar]
- Old JM, Varawalla NY, Weatherall DJ. Rapid detection and prenatal diagnosis of beta-thalassaemia: studies in Indian and Cypriot populations in the UK. Lancet. 1990 Oct 6;336(8719):834–837. [PubMed] [Google Scholar]
- Sommer SS, Cassady JD, Sobell JL, Bottema CD. A novel method for detecting point mutations or polymorphisms and its application to population screening for carriers of phenylketonuria. Mayo Clin Proc. 1989 Nov;64(11):1361–1372. [PubMed] [Google Scholar]
- Wenham PR, Newton CR, Price WH. Analysis of apolipoprotein E genotypes by the Amplification Refractory Mutation System. Clin Chem. 1991 Feb;37(2):241–244. [PubMed] [Google Scholar]
- Wu DY, Ugozzoli L, Pal BK, Wallace RB. Allele-specific enzymatic amplification of beta-globin genomic DNA for diagnosis of sickle cell anemia. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2757–2760. [PMC free article] [PubMed] [Google Scholar]
- Yokota I, Coates PM, Hale DE, Rinaldo P, Tanaka K. Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency. Am J Hum Genet. 1991 Dec;49(6):1280–1291. [PMC free article] [PubMed] [Google Scholar]
- Yokota I, Indo Y, Coates PM, Tanaka K. Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation. J Clin Invest. 1990 Sep;86(3):1000–1003. [PMC free article] [PubMed] [Google Scholar]