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(Circulation. 1995;91:1641-1646.)
© 1995 American Heart Association, Inc.

Articles

Genetic Diagnosis With the Denaturing Gradient Gel Electrophoresis Technique Improves Diagnostic Precision in Familial Hypercholesterolemia

Henrik Nissen, MD; Annebirthe Bo Hansen, MD; Per Guldberg, MSc; Niels Erik Petersen, MD; Mogens Lytken Larsen, MD; Torben Haghfelt, MD, DMSci; Karsten Kristiansen, MSc; Mogens Hørder, MD, DMSci

From the Department of Clinical Chemistry (H.N., A.B.H., N.E.P., M.H.) and the Department of Cardiology (M.L.L., T.H.), Odense University Hospital; the Department of Molecular Biology, Odense University (K.K.), Odense; and the John F. Kennedy Institute (P.G.), Glostrup, Denmark.

Correspondence to Henrik Nissen, MD, Department of Clinical Chemistry, Odense University Hospital, 5000 Odense C, Denmark.

Background Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder of lipid metabolism caused by mutations in the LDL receptor gene. FH is characterized clinically by elevated LDL cholesterol level and premature coronary disease. Diagnosing FH on clinical grounds may be difficult, and previous genetic methods are too cumbersome for routine use except in the few populations with FH-founder mutations. A simple mutation screening technique based on denaturing gradient gel electrophoresis (DGGE) has been highly useful in detecting mutations in other genes, and in the present study we evaluated the diagnostic potential of this method for the diagnosis of FH.

Methods and Results Conditions for screening exon 3 of the LDL receptor gene using the DGGE technique were established and 14 Danish FH families were examined. An index patient from 1 family had an abnormal DGGE pattern; consequently, an examination of exon 3 of the LDL receptor gene in 21 members of this patient's family was done. The DGGE pattern was seen only in patients with a definite clinical diagnosis of FH. Subsequent sequencing of exon 3 of the LDL receptor gene in these individuals revealed the presence of the French-Canadian type 4 Trp⁶⁶-Gly mutation. However, in 4 of 11 cases in which a definite clinical diagnosis of FH had been made, the inheritance of the French-Canadian type 4 mutation could be rejected on the basis of genetic analysis.

Conclusions Introduction of a simple genetic analysis based on DGGE may improve the precision of diagnosis in FH families.

Key Words: hypercholesterolemia • diagnosis • genes • molecular biology • arteriosclerosis