In search for genetic explanation for LDLc variabily in an FH family: Common SNPs and a rare mutation in microsomal triglyceride transfer protein explain only part of LDL variability in an FH family.

We previously identified a highly consanguineous FH family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect.LDLc values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a GWAS could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole-exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, MTTP R634C, into COS-7 cells, to test enzymatic activity.The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/mL) compared to wild-type allele (185.8 nmol/mL) (p=0.0012) and was marginally associated with reduced LDLc in FH patients (P=0.05).Phenotypic variability in an FH pedigree can only patrialy be explained by a combination of common SNPs and rare mutation and a rare variant in the MTTP gene. LDLc varianiily in FH patients may have non genetic causes.