title: Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.
abstract: BACKGROUND
  The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.
  
  
  METHODS
  We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening.
  
  
  RESULTS
  We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.
  
  
  CONCLUSIONS
  The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.
authors.affiliation: Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon; Department of GeneticsHarvard Medical School and Department of Internal MedicineMassachusetts General HospitalBostonMassachusetts.
authors.forename: Akl C
authors.initials: AC
authors.lastname: Fahed
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Ruby
authors.initials: R
authors.lastname: Khalaf
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Rony
authors.initials: R
authors.lastname: Salloum
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Rabih R
authors.initials: RR
authors.lastname: Andary
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Raya
authors.initials: R
authors.lastname: Safa
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Inaam
authors.initials: I
authors.lastname: El-Rassy
authors.affiliation: National LDL Apheresis Center Dahr El-Bashek Governmental University Hospital Roumieh Lebanon.
authors.forename: Elie
authors.initials: E
authors.lastname: Moubarak
authors.affiliation: Department of Internal Medicine American University of Beirut Beirut Lebanon.
authors.forename: Sami T
authors.initials: ST
authors.lastname: Azar
authors.affiliation: Department of Pediatrics and Adolescent Medicine American University of Beirut Beirut Lebanon.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Bitar
authors.affiliation: Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
authors.forename: Georges
authors.initials: G
authors.lastname: Nemer
keywords: Familial Hypercholesterolemia; LDLR; LDLRAP1; founder mutation