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Published on: September 15, 2018
Molecular diagnosis methods in familial hypercholesterolemia
Valeriu Moldovan1, Claudia Banescu1, Minodora Dobreanu1
1Advanced Center for Medical and Pharmaceutical Research, University of Medicine, Pharmacy, Science and Technology of Targu Mures; Targu Mures-Romania.
Insights
Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL cholesterol and early heart disease. Genetic testing, including sequencing, offers definitive diagnosis when clinical scores suggest FH, aiding cascade screening.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is a primary genetic cause of premature atherosclerotic cardiovascular disease.
- It results from mutations in genes like LDLR, APOB, and PCSK9, leading to elevated low-density lipoprotein cholesterol (LDL-C).
- Clinical diagnostic criteria and scoring systems exist but may not be exhaustive.
Purpose of the Study:
- To review and detail genetic techniques for identifying Familial hypercholesterolemia (FH).
- To emphasize the role of genetic diagnosis in confirming FH when clinical suspicion is present.
- To highlight the complementary nature of various genetic testing methods.
Main Methods:
- Review of genetic diagnostic techniques for FH.
- Discussion of single nucleotide polymorphism (SNP) genotyping.
- Explanation of multiplex ligation-dependent probe amplification (MLPA) analysis.
- Overview of Sanger sequencing and Next-Generation Sequencing (NGS).
Main Results:
- Genetic diagnosis provides unequivocal confirmation of FH.
- Despite mutation heterogeneity and polygenic factors, genetic testing is crucial.
- Clinical scores effectively identify individuals requiring genetic evaluation.
Conclusions:
- Genetic testing is essential for definitive FH diagnosis, complementing clinical assessments.
- Various genetic techniques, including sequencing, are vital for identifying causative mutations.
- Accurate genetic diagnosis facilitates cascade screening for affected families.
Abstract:
Familial hypercholesterolemia (FH) is considered the genetic cause of coronary heart disease and ischemic stroke. FH is mainly an autosomal codominant pattern-based disorder and is primarily determined by point mutations within the low-density lipoprotein receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes, causing increased low-density lipoprotein cholesterol levels in the serum of untreated individuals. The accumulation will eventually lead to atherosclerotic cardiovascular disease. Although clinical criteria comprising several prognosis scores, such as the Simon Broome, Dutch Lipid Clinic Network, Make Early Diagnosis to Prevent Early Death, and the recently proposed Montreal-FH-SCORE, are the conventional basis of diagnosing FH, the genetic diagnosis made by single nucleotide polymorphism genotyping, multiplex ligation-dependent probe amplification analysis, and sequencing (both Sanger and Next-Generation sequencing) offers unequivocal diagnosis. Given the heterogeneity of known mutations, the genetic diagnosis of FH is often difficult to establish, despite the growing evidence of the causative mutations, as well as the polygenic aspect of this pathology and the importance of cascade screening of the FH patient‚s healthy family members. This review article details different genetic techniques that can be used in FH identification when there is a clinical FH suspicion based on criteria comprised in prognosis scores, knowing that none of these are exhaustive in the diagnosis, yet they efficaciously overlap and complement each other for confirming the disease at the molecular level.
