Genetic diagnosis of familial hypercholesterolemia in affected relatives using pedigree tracing

Objectives: To describe a process of diagnosing familial hypercholesterolemia (FH) at the DNA level in selected family members of affected individuals. Design and Methods: A 63-year-old male patient presented with cholesterol elevations consistent with heterozygous familial hypercholesterolemia. Through participation with the international “MED-PED FH” project to detect affected relatives and to identify their LDL-receptor mutation, the patient was discovered to carry the Lebanese mutation, whereby the codon for cysteine at residue 660 instead codes for a premature termination (C660X), thus truncating the protein product. This mutation also created a new restriction recognition site for the endonuclease Hinfl, which permitted rapid detection of the mutation in selected family members using restriction fragment-length polymorphisms. Results: The patientʹs son, who had cholesterol levels consistent with heterozygous FH, was also found to be a heterozygote for the C660X variant of the LDL-receptor. Conclusions: Diagnosis of familial hypercholesterolemia at the DNA level is possible as a relatively rapid screening technique in families with a known LDL-receptor mutation, established through participation with the MED-PED FH project.