Projects / Programmes
IDENTIFICATION OF GENETIC CAUSES OF DYSLIPIDEMIAS IN CHILDREN AND ADOLESCENTS AND THEIR EARLY DETECTION WITH UNIVERSAL SCREENING PROGRAM
| Code |
Science |
Field |
Subfield |
| 3.07.00 |
Medical sciences |
Metabolic and hormonal disorders |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
dyslipidemia, rare dyslipidemias, poligenic hypercholesterolemia, familial hypercholesterolemia, rare diseases, genetics, familial hypercholesterolemia screening
Researchers (27)
Organisations (1)
Abstract
Familial hypercholesterolemia (FH) is the most common life-threatening inherited metabolic disorder and is linked to three genes LDLR, APOB, and PCSK9. The incidence of FH is around 1/250, but over 90% of patients in the developed world are undiagnosed. FH is characterised by a markedly elevated level of LDL (low-density lipoprotein) cholesterol from birth onwards, and thus causing accelerated atherosclerosis leading to premature cardiovascular complications. According to the most recent data, a patient with undiagnosed FH loses an average of 16 years of life. Early diagnosis, ideally in the context of population screening, is crucial to reduce the risk of cardiovascular complications, as effective, safe and cost-effective treatment is available. In Slovenia, we detect FH by screening all 5-year-old children, thus detecting the majority of all patients in the population, which is currently the only such population screening program for FH globally. Indirectly, within the population screened for FH, we also detect individuals with marked polygenic hypercholesterolemia or rare dyslipidemias (hypocholesterolemia, lysosomal acid lipase deficiency, inherited elevation of Lipoprotein(a) (Lp (a)), etc.). Polygenic hypercholesterolemia is caused by changes (or combinations of changes) in more than 100 different genes, with more pronounced cases being expressed as early as childhood. Rare dyslipidemias are a genetically and clinically heterogeneous group of inherited metabolic disorders and dozens of causal genes are currently known. Causal changes in LDLR, APOB, and PCSK9 genes during genetic testing (and thus confirmed FH) are detected in only about 40% of patients with dyslipidemia referred for FH population screening (e.g., in 2018, about 150 children were referred for further genetic analysis and out of them 60 had confirmed FH). However, the genetic cause of the other subjects has not yet been clarified, so we want to extend their genetic characterisation and try to identify the genetic cause of their dyslipidemia. Two main objectives of the project are: (1) to find new genetic variants involved in dyslipidemia with advanced next-generation sequencing technology (NGS), which enables the analysis of multiple genes simultaneously and (2) to develop a method to enable the routine and cost-effective genetic analysis of polygenic causes of hypercholesterolemia (to determine »polygenic score«) and at same time to enable genetic analysis of wide spectrum of rare dyslipidemias (those with hyper- and hypo-cholesterolemia). The method will be subsequently implemented in the universal screening program for cholesterol to detect the patients with rare dyslipidemias where the early detection is feasible and beneficial for early treatment. Thus, we want to identify causative variants in known genes associated with hypercholesterolemia and other primary dyslipidemias and to look for changes in potential other, yet unknown causal genes. According to data from the literature, we will expand the existing panel of genes associated with hypercholesterolemia, with causal genes for the most important rare dyslipidemias (abetalipoproteinemia, hypobetalipoproteinemia, lysosomal acid lipase deficiency, primary hypertriglyceridemia, sitosterolemia, hypoalphalipoproteinemia, hyperchylomicronemia, inherited elevation of Lipoprotein(a), etc.). However, we expect that, despite a larger set of analyzed genes, we will still not explain the genetic status of all patients, therefore in individuals with prominent phenotypes we will attempt to identify a polygenic cause based on the results of previous genome-wide association studies (GWAS) and/or perform an additional Whole-exome sequencing (WES) or Whole genome sequencing (WGS) in selected patients to identify changes in potential other, yet unknown causal genes. Genetic variations of unknown significance will be further evaluated with commercially available expression models.
