Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.

Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p.(W577C) and frameshift p.(G676Afs33) variants at exons 12 and 14 of the LDLR gene respectively. DNA sequencing of LDLR gene from the parents demonstrated that the missense variant was inherited from the mother and frameshift variant was inherited from the father. The frameshift variant resulted in a stop signal 33 codons downstream of the deletion, which most likely led to a truncated protein that lacks important functional domains, including the trans-membrane domain and the cytoplasmic tail domain. The missense variant is also predicted to be likely pathogenic and affect EGF-precursor homology domain of the LDLR protein. The segregation pattern of the variants was consistent with the lipid profile, suggesting a more severe FH phenotype when the variants are in the compound heterozygous state. The finding of a compound heterozygous mutation causing severe FH phenotype is important for the genotype-phenotype correlation and also enlarges the spectrum of FH-causative LDLR variants in the Arab population, including the Saudi population.

Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.

Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.

Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia.

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 who were resistant to statin therapy and were managed on an apheresis program. 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.