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Genetic diagnosis of familial hypercholesterolemia in affected relatives using pedigree tracing
S H Hsia1, P W Connelly, R A Hegele
1Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada.
Insights
DNA testing can rapidly diagnose familial hypercholesterolemia (FH) in relatives. Identifying the specific LDL-receptor mutation, like C660X, allows for quick genetic screening within affected families.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Familial hypercholesterolemia (FH) is an inherited disorder characterized by high cholesterol levels.
- Genetic defects in the LDL-receptor gene are a primary cause of FH.
- Early diagnosis and intervention are crucial for managing cardiovascular risk in FH patients.
Observation:
- A patient with heterozygous FH was found to carry the Lebanese mutation (C660X) in the LDL-receptor gene.
- This specific mutation (C660X) created a new restriction site for the endonuclease Hinfl.
- Restriction fragment-length polymorphism (RFLP) analysis using Hinfl enabled rapid detection of the C660X mutation.
Findings:
- The C660X mutation leads to a truncated LDL-receptor protein.
- The patient's son, also diagnosed with heterozygous FH, was identified as a carrier of the C660X LDL-receptor variant.
- DNA-level diagnosis proved effective in identifying affected family members.
Implications:
- DNA-based diagnosis offers a rapid screening method for FH within families.
- Identifying specific mutations like C660X facilitates targeted genetic testing.
- This approach aids in early detection and management of FH, potentially reducing cardiovascular events.
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 "MEDPED 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 patient's 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.