Phenotypic presentation of the FH-Cincinnati type 5 low density lipoprotein receptor mutation
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Phenotypic presentation of the FH-Cincinnati type 5 low density lipoprotein receptor mutation. / Nissen, H; Hansen, A B; Guldberg, P; Petersen, N E; Larsen, M L; Haghfelt, T; Kristiansen, K; Hørder, M.
In: Scandinavian Journal of Clinical & Laboratory Investigation, Vol. 56, No. 1, 1996, p. 75-85.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Phenotypic presentation of the FH-Cincinnati type 5 low density lipoprotein receptor mutation
AU - Nissen, H
AU - Hansen, A B
AU - Guldberg, P
AU - Petersen, N E
AU - Larsen, M L
AU - Haghfelt, T
AU - Kristiansen, K
AU - Hørder, M
N1 - Keywords: Base Sequence; Codon; Electrophoresis; Genotype; Humans; Hypercholesterolemia; Molecular Sequence Data; Mutation; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Receptors, LDL
PY - 1996
Y1 - 1996
N2 - Familial hypercholesterolaemia (FH) is an autosomal dominant hereditary disease of lipid metabolism that in most families is caused by mutations in the low density lipoprotein receptor (LDLR) gene. Though more than 150 mutations are known, the clinical picture associated with most of these is not known. Genetic FH diagnosis may soon become routine in the setting of genetic counselling, and therefore thorough information on the phenotype-genotype relationship of different mutations is now important. In this study, index patients from each of 14 Danish FH families were screened for mutations in exon 2 of the LDLR gene using a denaturing gradient gel electrophoresis (DGGE)-based mutation screening assay. A deviating DGGE pattern identified two index patients, where subsequent sequencing revealed heterozygosity for the FH Cincinnati type 5 Trp23-to-Stop LDLR mutation. Data from three generations of the families allowed the first clinical and biochemical description of this mutation. Evidence that genetic analysis adds independent diagnostic information compared to traditional clinical/biochemical FH diagnosis was documented by demonstrating the presence of the FH Cincinnati mutation in a family member with a completely normal lipid profile. By comparison to non-FH family members, it was documented that carrier status for the FH Cincinnati mutation is associated with a significant risk of cardiovascular disease. Thus, genetic analysis may improve diagnostic precision and help to define more precisely which of the members of FH families are in need of preventive interventions and may aid in establishing phenotype-genotype relationships allowing more refined genetic counselling in FH.
AB - Familial hypercholesterolaemia (FH) is an autosomal dominant hereditary disease of lipid metabolism that in most families is caused by mutations in the low density lipoprotein receptor (LDLR) gene. Though more than 150 mutations are known, the clinical picture associated with most of these is not known. Genetic FH diagnosis may soon become routine in the setting of genetic counselling, and therefore thorough information on the phenotype-genotype relationship of different mutations is now important. In this study, index patients from each of 14 Danish FH families were screened for mutations in exon 2 of the LDLR gene using a denaturing gradient gel electrophoresis (DGGE)-based mutation screening assay. A deviating DGGE pattern identified two index patients, where subsequent sequencing revealed heterozygosity for the FH Cincinnati type 5 Trp23-to-Stop LDLR mutation. Data from three generations of the families allowed the first clinical and biochemical description of this mutation. Evidence that genetic analysis adds independent diagnostic information compared to traditional clinical/biochemical FH diagnosis was documented by demonstrating the presence of the FH Cincinnati mutation in a family member with a completely normal lipid profile. By comparison to non-FH family members, it was documented that carrier status for the FH Cincinnati mutation is associated with a significant risk of cardiovascular disease. Thus, genetic analysis may improve diagnostic precision and help to define more precisely which of the members of FH families are in need of preventive interventions and may aid in establishing phenotype-genotype relationships allowing more refined genetic counselling in FH.
U2 - 10.3109/00365519609088591
DO - 10.3109/00365519609088591
M3 - Journal article
C2 - 8850176
VL - 56
SP - 75
EP - 85
JO - Scandinavian Journal of Clinical & Laboratory Investigation
JF - Scandinavian Journal of Clinical & Laboratory Investigation
SN - 0036-5513
IS - 1
ER -
ID: 11253640