Deletion in the Gene for the Low-Density-Lipoprotein Receptor in a Majority of French Canadians with Familial Hypercholesterolemia

We found a large deletion (more than 10 kilo-bases) in the gene for the low-density-lipoprotein receptor in 63 percent of French Canadians with heterozygous familial hypercholesterolemia. The deletion also occurred in homozygous form in four of seven French Canadian homozygotes. The deletion removes the promoter and first exon of the gene, and it abolishes the production of messenger RNA for the low-density-lipoprotein receptor. The high frequency of this mutation is presumably related to a founder effect among the 8000 ancestors of present-day French Canadians, who have had relatively little cross-breeding with groups of other national origins. This deletion has not been observed in any other ethnic group. It can be detected by analysis of genomic DNA from blood leukocytes, thus allowing direct diagnosis of familial hypercholesterolemia in a majority of affected French Canadians. (N Engl J Med 1987; 317: 734–7.) THE examination of mutant human genes at a molecular level has revealed that inherited diseases are usually heterogeneous. Each disease can be produced by any of several mutations in a single gene or in a related set of genes. Heterogeneity of mutations within a single gene has been suggested by studies of the mutant proteins in the thalassemias and in glucose-6-phosphate dehydrogenase deficiency.¹ With the development of recombinant DNA techniques, this type of heterogeneity has been found to affect many mutant genes, including those responsible for the Lesch–Nyhan syndrome² and for hemophilia A.^3,4 Genetic heterogeneity has created a problem in.