Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy

Akl C Fahed; Ruby Khalaf; Rony Salloum; Rabih R Andary; Raya Safa; Inaam El-Rassy; Elie Moubarak; Sami T Azar; Fadi F Bitar; Georges Nemer

doi:10.1002/mgg3.203

Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy

Mol Genet Genomic Med. 2016 Feb 24;4(3):283-91. doi: 10.1002/mgg3.203. eCollection 2016 May.

Authors

Affiliations

¹ Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon; Department of GeneticsHarvard Medical School and Department of Internal MedicineMassachusetts General HospitalBostonMassachusetts.
² Department of Biochemistry and Molecular Genetics American University of Beirut Beirut Lebanon.
³ National LDL Apheresis Center Dahr El-Bashek Governmental University Hospital Roumieh Lebanon.
⁴ Department of Internal Medicine American University of Beirut Beirut Lebanon.
⁵ Department of Pediatrics and Adolescent Medicine American University of Beirut Beirut Lebanon.

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.

Conclusion: 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.

Keywords: Familial Hypercholesterolemia; LDLR; LDLRAP1; founder mutation.