Abstract 18262: Molecular Genetics of Familial Hypercholesterolemia in Israel Revisited
Background: In 1996, the first summary of molecular genetics of familial hypercholesterolemia (FH) in Israel was published (Reshef A, Hum Gen, 1996). Since then, new technology for mutation screening became available making genetic diagnosis easier more accurate, and more comprehensive. We performed systematic mutation screening of index cases of 68 pedigrees to reanalyze the profile of mutations among Israeli FH patients.
Methods and results: In 68 individuals the entire coding region, promoter and intron-exon junctions of the LDLR and part of exon 26 of the APOB gene were screened for variants using High Resolution Melting, with Sanger sequencing of any identified melt shifts. Mutations of the LDLR gene were found in twenty-three patients (34% of the total) with seventeen different mutations . The most common mutation was p.(V827I) (47% of the detected mutations), not previously reported in Refech et al but reported to occur in patients from Russia. Three variants, two in exon 4 and one in the promoter region were not reported before; p.(C121S), p.(E140A) and c.-191 C>A. One patient carried the common APOB p.(R3527Q) mutation. 70% of the cohort were negative for an LDLR or APOB mutation. It was hypothesized that FH can be caused by an accumulation of LDL-C raising alleles each having a small contributive effect (Talmud et al., 2013). Using this published gene score method derived from twelve common LDL-C raising SNPs in eleven genes, the mean polygene score was significantly higher (p=0.03) among mutation negative Israeli FH patients compared with a European control population.
Conclusion: We identified mutations in 30% of a new Israeli FH cohort. In these we found 3 novel LDLR mutations. The high prevalence of p.(V827I) likely reflects the change in demographics of the Israeli population since 1996 . In the remaining mutation free cohort, there is likely to be a polygenic cause of their elevated LDL-C and FH diagnosis. These data can help design a future strategy for early screening for FH in our population.
Author Disclosures: R. Durst: None. U. Ibe: None. V. Meiner: None. S. Shpitzen: None. D. Schurr: None. O. Eliav: None. M. Futema: None. R. Whittall: None. S.E. Humphries: None. E. Leitersdorf: None.
- © 2014 by American Heart Association, Inc.