title: Molecular genetics of familial hypercholesterolemia in Israel-revisited.
abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel.
  
  
  
  New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes was done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping.
  
  
  
  Mean serum cholesterol was 7.48 ± 1.89 mmol/L and the mean serum LDL-C was 5.99 ± 1.89 mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q), in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C > A. The c.2479G > A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C, but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a "mild" FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p = 0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy.
  
  
  
  The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.
authors.affiliation: Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel; Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Electronic address: durst@hadassah.org.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Durst
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Uche Ken
authors.initials: UK
authors.lastname: Ibe
authors.affiliation: Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Shoshi
authors.initials: S
authors.lastname: Shpitzen
authors.affiliation: Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schurr
authors.affiliation: Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Eliav
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Whittall
authors.affiliation: Internal Medicine Department, Mount Scopus, Hadassah Hebrew University Medical Center, Israel.
authors.forename: Auryan
authors.initials: A
authors.lastname: Szalat
authors.affiliation: Department of Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.affiliation: Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot, Israel.
authors.forename: Hilla
authors.initials: H
authors.lastname: Knobler
authors.affiliation: Department of Medicine, Wolfson Medical Center, Holon, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Gavish
authors.affiliation: Department of Cardiology, Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Henkin
authors.affiliation: Internal Medicine, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Avishay
authors.initials: A
authors.lastname: Ellis
authors.affiliation: Department of Metabolic Clinic, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Ardon
authors.initials: A
authors.lastname: Rubinstein
authors.affiliation: Bert W. Strassburger Lipid Center, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
authors.affiliation: Bert W. Strassburger Lipid Center, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bitzur
authors.affiliation: Maccabi Health Services, Israel.
authors.forename: Bruno
authors.initials: B
authors.lastname: Hershkovitz
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Center for Research Prevention and Treatment of Atherosclerosis, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100 / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D007557:Israel; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D055815:Young Adult
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D015415:Biomarkers; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Familial hypercholesterolemia; Hyperlipidemia; LDL receptor; LDLR mutation