Genetic diagnosis of familial hypercholesterolaemia: a mutation and a rare non-pathogenic amino acid variant in the same family.

Familial hypercholesterolaemia (FH), a relatively common inherited disorder, is caused by mutations in the gene for the low density lipoprotein (LDL) receptor (LDLR) that result in impaired clearance of LDL. Identification of mutations in patients with the clinical phenotype of FH allows unequivocal diagnosis in potentially affected relatives, but depends critically on distinguishing mutations that affect protein function from variants with no significant effect. A presumed functional mutation in LDLR (G198D in exon 4) was identified in two hypercholesterolaemic English brothers by high throughput screening and was not found in 550 controls. However, a second variant (L458P) was identified separately in their mother that co-segregated with hypercholesterolaemia in the entire pedigree. L458, but not G198, is strongly conserved between species and lies in a region important for beta-propeller stability. G198D was inherited from their normolipidaemic father by two of three siblings heterozygous for L458P; they appeared less severely hypercholesterolaemic and more responsive to statins than the third affected brother and their mother. This study emphasises that apparent co-segregation of an amino acid substitution in a critical region of the protein with hypercholesterolaemia and its absence from a large control population is insufficient evidence that a variant of the LDL receptor is necessarily deleterious to its function.