Open AccessVariable expressivity and co‐occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy
Author(s) -
Fahed Akl C.,
Khalaf Ruby,
Salloum Rony,
Andary Rabih R.,
Safa Raya,
ElRassy Inaam,
Moubarak Elie,
Azar Sami T.,
Bitar Fadi F.,
Nemer Georges
Publication year - 2016
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.203
Subject(s) - familial hypercholesterolemia , expressivity , genetics , medicine , ldl receptor , biology , cholesterol , lipoprotein
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 ( LDLRAP 1 ), 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 LDLRAP 1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes. Conclusion The p.Q136* variant in LDLRAP 1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.