Aim
Whole exome sequencing could allow us to discover new genes involved in the familial hypercholesterolemia (FH).
Methods
We selected 200 patients (169 unrelated and 31 family members) with LDLc levels, corrected by Lp(a) concentrations, >220 mg/dL, without functional mutation in candidate genes and with a clear autosomal dominant pattern of hypercholesterolemia transmission within the family from the Lipid Unit at Hospital University Miguel Servet, Spain for whole-exome sequencing. First, we checked all loss-function and missense variants predicted to be damaging by computer prediction algorithms in LDLR and all rare variants annotated as pathogenic in human genetics database (ClinVar) in PCSK9, LDLR and APOB genes. We analysed the binding between LDLc-LDLr in all FH subjects by ELISA. Second, we did a family analysis, looking for pathogenic rare variants present in all affected family members and not present in non-affected family members. Third, we ran single variant association using firth logistic regression to compare our cases with controls from the REGICOR and MDC studies with LDLc ≤ 150 mg/dL.
Results
We found one patient who carrier the pathogenic mutation in LDLR, p.(Asp175Gly), not previously associated with FH. In the APOB gene, we found three pathogenic mutations (p.(Lys3344Glu), p.(Ala3396Val), p.(Gly3054Arg)), not previously associated with FH, in patients with affected binding. Family analysis reported one loss-function variant in the BRD7 gene. BRD7 gene has been previously associated with atherosclerosis development. 
Conclusions
We found new missense variants in LDLR and APOB and a new gene (BRD7) which could be involved in FH

04 - WHOLE-EXOME SEQUENCING IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA WITHOUT FUNCTIONAL MUTATION IN CANDIDATE GENES.