Defining the genetic eriology of dyslipdemias

Background : Atherosclerosis is the leading causing dearth in western countries. Dyslipidemias pose a major risk factor for atherosclerosis. Our lab is working on defining the genetic causes for dyslipidemias in the Israeli population.Materials and Methods : Families and individuals with suspected genetic forms of dyslipidemia were collected through the MED PED (Make Early Diagnosis Prevent Early Death) FH program. SNP scores were used to define the risk for mutation negative FH patietns. Molecular analysis is preformed to define the etiology of the disease. In case of doubt, we generate a reporting assay to define the pathogenicity of the mutations.Results : Mutations in the LDLR and APOB gene were found in 23 cases, 17 different mutations in the LDLR and two, p.R3527Q and p.R3558C in APOB . Of the LDLR mutation, four were novel (p.(E140A), p.(C121S), a promoter variant, c.-191C>A, and a major deletion in exons 7-14. No PCSK9 mutations were identified. A higher LDL-C SNP score was found in mutation-negative cases compared with a normal Caucasian cohort. We have identified rare forms of dyslipidemia causes, such as the case of APOE Kochi variant (APOE: c.488G > A; p.Arg163His). We have identified a mutation in MTTP causing LDLc normalization in an FH family.

Conclusions : The results indicate a high diversity of LDLR and APOB mutations, in concordance with the heterogeneous origin of the Israeli population. The results provide a valuable addition to current diagnostic tools for a subset of the Israeli patients with FH who are at high risk for atherosclerosis and its complications.