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Phenotype of definite familial hypercholesterolemia with negative genetic study in Argentina
Pablo Corral1, Virginia Bañares2, Benjamín Sáenz3
1Cátedra de Farmacología, Facultad de Medicina, Universidad FASTA. Buenos Aires, Argentina.
Insights
A significant portion of patients with definite familial hypercholesterolemia (FH) showed no genetic alteration. This highlights potential gaps in current genetic testing for FH, suggesting new genes or environmental factors may be involved.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is a monogenic disorder impacting lipid metabolism.
- Genetic variants in LDLR, APOB, and PCSK9 genes are primary causes of FH.
- Clinical diagnosis relies on criteria like the Dutch Lipid Clinic Network (DLCN) score, with >8 indicating definite FH.
Purpose of the Study:
- To investigate the genetic underpinnings of hypercholesterolemia in Argentinian patients.
- To evaluate the diagnostic yield of next-generation sequencing (NGS) and polygenic risk scores in definite FH cases.
- To identify potential reasons for genetic variants not being detected in clinically diagnosed FH patients.
Main Methods:
- The Da Vinci Study evaluated 246 hypercholesterolemic patients in Argentina.
- Twenty-one patients with a DLCN score >8 underwent genetic analysis.
- Methods included NGS with a 23-gene panel, large rearrangement analysis, and a 10 single nucleotide polymorphism (SNP) polygenic score.
Main Results:
- Of 21 definite FH patients, 10 had variants in LDLR, 1 in APOB, 1 in LIPC, and 2 had LDLR rearrangements.
- One patient with LDLR alterations also had a LIPA variant.
- Notably, 6 out of 21 (28.6%) patients with a definite clinical FH diagnosis had no detectable genetic alterations.
- One patient with an APOB variant also had an APOE variant.
Conclusions:
- A substantial percentage of clinically diagnosed FH patients lack identifiable genetic variants using current methods.
- This discrepancy may be attributed to mutations in novel genes, environmental influences, gene-gene interactions, or limitations in detection technologies.
- Further research is needed to elucidate the genetic and environmental factors contributing to FH in these cases.
Objective:
Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment.
Methods:
In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c.
Results:
Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration.
Conclusions:
We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.
