HEREDITARY TYROSINEMIA TYPE-I - STRONG ASSOCIATION WITH HAPLOTYPE-6 IN FRENCH-CANADIANS PERMITS SIMPLE CARRIER DETECTION AND PRENATAL-DIAGNOSIS

Hereditary tyrosinemia type 1 (HT1), a severe inborn error of tyrosine catabolism, is caused by deficiency of the terminal enzyme, fumarylac etoacetate hydrolase (FAH). The highest reported frequency of HT1 is i n the French Canadian population, especially in the Saguenay-Lac-St-Je an region. Using human FAH cDNA probes, we have identified 10 haplotyp es with TaqI, KpnI, RsaI, BglII, and MspI RFLPs in 118 normal chromoso mes from the French Canadian population. Interestingly, in 23 HT1 chil dren, a prevalent haplotype, haplotype 6, was found to be strongly ass ociated with the disease, at a frequency of 90% of alleles, as compare d with similar to 18% in 35 control individuals. This increased to 96% in the 24 patients originating from Saguenay-Lac-St-Jean. These resul ts suggest that one or only a few prevailing mutations are responsible for most of the HT1 cases in Saguenay-Lac-St-Jean. Since most patient s were found to be homozygous for a specific haplotype in this populat ion, FAH RFLPs have permitted simple carrier detection in nine differe nt informative HT1 families, with a confidence level of 99.9%. Heteroz ygosity rate values obtained from 52 carriers indicated that similar t o 88% of families at risk from Saguenay-Lac-St-Jean are fully or parti ally informative. Prenatal diagnosis was also achieved in an American family. Analysis of 24 HT1 patients from nine countries gave a frequen cy of similar to 52% for haplotype 6, suggesting a relatively high ass ociation, worldwide, of HT1 with this haplotype.