Estimation of the Incidence of a Rare Genetic Disease Through a Two-Tier Mutation Survey

Authors

R Chakraborty
M R Srinivasan
S Raskin

Publication Date

6-1-1993

Journal

American Journal of Human Genetics

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.

Keywords

Acyl-CoA Dehydrogenase, Acyl-CoA Dehydrogenases, Cystic Fibrosis, Genes, Recessive, Genetics, Population, Heterozygote, Humans, Incidence, Models, Genetic, Mutation

PMID

8503445

PMCID

PMC1682293

PubMedCentral® Posted Date

June 1993

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes