039 0.5 0.193 0.05 0.1 0.076 0.5 0.380 Table 2 shows the results of calculations of the frequencies of homozygotes IBD and non-IBD among affected Tyrosine Kinase Inhibitor Library supplier children of first cousins, and the total frequency of pathogenic alleles in the population in case of 10% compound heterozygotes and with different numbers and relative frequencies of pathogenic alleles. As the proportion of compound heterozygotes is fixed at 10% in this table, the row sum of the proportions of homozygotes IBD and non-IBD (third and fourth columns) add up to 90%. The table shows that knowledge of the proportion of compound heterozygotes, the inbreeding

coefficient, and the number and relative frequencies of pathogenic alleles (first and second columns) allows one to calculate the total frequency of pathogenic alleles of a gene in the population (fifth column). Not unexpectedly, the higher the frequency of the major allele, the higher is the frequency of homozygotes non-IBD and the higher the total frequency of pathogenic alleles in the population for a given frequency of compound heterozygotes among affected offspring of consanguineous matings. The same trend can be observed for children of second cousins (data not shown) and other levels of inbreeding. Table 2 Frequencies of homozygotes IBD and non-IBD among children with an autosomal recessive disease whose parents

are first cousins when 10% of these children are compound heterozygotes as well as total frequency of pathogenic alleles in the population for different selleck inhibitor numbers and relative frequencies of alleles Input Output Alleles Frequencies among affected children Total frequency of pathogenic alleles in the population Number Relative

frequency Homozygotes IBD Homozygotes non-IBD 5 0.9; 0.07; 0.02; 0.007; 0.003 0.458 0.442 0.079 0.7; 0.2; 0,05; 0.03; 0.02 0.786 0.114 0.018 0.5; 0.3; 0.1; 0.07; 0.03 0.845 0.055 0.012 0.4; 0.3; 0.2; 0,08; 0.02 0.858 0.042 0.011 0.2; 0.2; 0.2; 0.2; 0.2 0.875 0.025 0.010 3 0.9; 0.07; 0.03 0.457 0.443 0.079 0.7; 0.2; 0.1 0.783 0.117 0.018 0.33333; 0.33333; 0.33333 0,850 0.050 0.012 2 0.9; 0.1 0.444 0.456 0.083 0.7; 0.3 0.762 0.138 0.021 0.5; 0.5 0.800 0.100 0.017 Discussion Since our observation of a compound heterozygous CF patient with consanguineous parents back Methisazone in 1990, many more observations of compound heterozygotes in consanguineous families have been reported (summarized in Petukhova et al. 2009). Such patients present a problem to researchers using autozygosity mapping for identification of recessive disease genes. Still, finding compound heterozygosity among affected children of consanguineous couples has potential advantages. It may comfort parents, who thought or were told that their consanguinity was causally related to the disorder in their children, to learn now that their consanguinity cannot be blamed for it. The same applies to some extent for parents who can be told that there is a considerable chance that the homozygosity in their affected child is not caused by alleles IBD.