Estudo de dislipidemias familiares de causa monogénica rara e poligénica

Dyslipidaemia is one major risk factors for cardiovascular disease (CVD), which is the leading cause of death in Portugal and worldwide. The identification the origin of the dyslipidaemia improves patient outcomes since, depending on the affected pathway, a more personalized treatment can be offered to avoid the consequences of the lipid metabolism disruption. The molecular diagnosis of the different types of dyslipidaemia allows the correct diagnosis in which treatment can be based. There are two major groups within the vast theme of dyslipidaemia: hypercholesterolaemias and hypertriglyceridaemias. Familial hypercholesterolaemia (FH), an autosomal dominant disorder, is the most common monogenic disorder associated with an increased cardiovascular risk with a prevalence of 1/250-1/500. For this reason, the identification of patients with FH should be a health priority. Three genes have been associated to FH: LDLR, APOB, PCSK9. Familial hypertriglyceridaemias also confers a high cardiovascular risk as in Familial Combined Hyperlipidaemia (FCHL), a polygenic disorder, or can lead to other complications, as pancreatitis, in Familial Lipoprotein Lipase Deficiency (FLLD), an autosomal recessive disorder due to mutations in LPL or its co-factor APOC2. There are also other rare recessive dyslipidaemia associated with low levels (below the 5th percentile for age and sex) of one or more lipid particles namely LDL, HDL and triglycerides. Dyslipidaemia presenting low LDL levels can be due to stop mutations in APOB (hypobetalipoproteinaemia, FHBL) or mutations in MTTP gene (abetalipoproteinaemia, ABL), two autosomal recessive disorders. Patients these two disorders may manifest a variety of symptoms and signs affecting several organs (steatorrhea, neurological and ophthalmological symptoms, non-alcoholic fatty liver disease). Another group of dyslipidaemia are the ones that cause low HDL values (below the 5th percentile for age and sex) and usually presents with increase cardiovascular risk. The best know is Tangier disease, an autosomal recessive disorder caused by mutations in ABCA1 gene and HDL deficiency, an autosomal dominant disorder caused by mutations in ABCA1 and APOA1 genes. At the National Institute of Health dyslipidaemia diagnosis is performed at present time by Next Generation Sequencing with 4 different panels: the FH panel (LDLR, APOB, PCSK9, LDLRAP1, LIPA, APOE and ABCG5/8 genes); Familial Hypertriglyceridaemia panel (LPL, APOC2, APOA5, APOC3, LMF1, GPD1, LIPA, GPIHBP1 and APOE genes); Disorders associated with HDL panel (APOA1, ABCA1, LCAT, CETP and SCARB1 genes); and Disorders associated with low LDL panel (APOB, MTTP, PCSK9, ANGPTL3 and SAR1B genes). We also perform extensive biochemical characterization including TC, C-HDL, C-LDL, TG, apolipoprotein AI, AII, B, CII, CIII, E and sdLDL that enables a better identification of the pathway affect and can direct towards the most suitable molecular study.N/