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A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia
P N Hopkins1, L L Wu, S H Stephenson
1Cardiovascular Genetics Research Clinic, University of Utah Medical School, Salt Lake City 84108, USA. paul@ucvg.med.utah.edu
Insights
Accurate diagnosis of heterozygous familial hypercholesterolemia (FH) is crucial. Genetic testing identified a novel mutation in the LDL receptor gene, enabling precise FH diagnosis in a Utah family.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is an inherited disorder causing high LDL cholesterol and early heart disease.
- Current diagnostic criteria for FH have limitations in accuracy for both family screening and general populations.
- Accurate, genetically validated criteria are needed for early FH diagnosis.
Purpose of the Study:
- To develop and validate accurate genetic criteria for diagnosing heterozygous familial hypercholesterolemia (FH).
- To identify novel mutations within the LDL receptor gene (LDLR) associated with FH.
Main Methods:
- Screening of all 18 exons and exon-intron boundaries of the LDLR gene for mutations.
- Utilizing a novel point mutation (C-to-T transversion at nucleotide position 631) in the LDLR gene.
- Employing mutant allele-specific amplification for genetic diagnosis in family members.
Main Results:
- Identification of a novel point mutation in the LDLR gene (c.631C>T; p.His190Tyr) in the proband.
- Accurate diagnosis of 7 individuals as heterozygous for the identified LDLR mutation.
- Exclusion of 5 individuals from FH carrier status based on genetic testing.
Conclusions:
- The identified LDLR mutation provides a precise genetic marker for FH diagnosis.
- Mutant allele-specific amplification is effective for diagnosing FH within families.
- Genetically validated criteria improve diagnostic accuracy for heterozygous FH.
Abstract:
Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.