4. Identification of a novel nonsense variant C.1332DUP, P. (D445*) in the LDLR gene that causes familial hypercholesterolemia

Abstract

Basic Science Research. Presentation type: Digital Poster. Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disease predominantly caused by a mutation in the low-density lipoprotein receptor (LDLR) gene. Here, we describe two severely affected FH patients from the same Saudi family, who were resistant to statin therapy and were managed on an apheresis program. Methodology: Two proband samples were collected from the patients. Direct sequencing of the LDLR gene was performed by using the Sanger sequencing method. Results: We identified a novel duplication variant c.1332dup, p. (D445*) at exon 9 and a known silent variant c.1413A>G, p. (=), rs5930, NM_001195798.1 at exon 10 of the LDLR gene in both patients. Both probands were homozygous for the mutation, which is located in the EGF-precursor homology domain of the LDLR protein, and show severe FH phenotype. Conclusion: The duplication variant results in the production of a defective LDL receptor containing the p. (D445*) variant. This variant results in a premature stop codon at position 445 in exon 9 of the LDLR gene, which results in truncation of the protein. The segregation pattern of the variant is consistent with the lipid profile, suggesting a more severe FH phenotype when the variant is in the homozygous state. Finding of this study could be very useful in developing critical genetic screen for potential FH patients. In addition, these data contribute to the understanding of the molecular basis of FH in Saudis.