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

71. Incidence of paravalvular leakage after aortic and mitral valve replacement at KFSH & RS, single centre experience

Paravalvular leakage (PVL) is not rare and can be a serious clinical problem in 1–5% of all valve replacement. There are inconclusive data regarding the incidence of PVR after aortic valve replacement (AVR) and mitral valve replacement (MVR).The aim of this study was to review PVL based upon more than ten years experience from King Faisal Specialist Hospital & Research Centre. Method: Retrospective analysis of the consecutive adult patients that underwent surgical valve replacement between January 2000 and December 2011. Results: During the period of 12 years (January 2000 through December 2011), prosthetic valve replacement surgery was performed in 2060 patients, aortic valve replacement (AVR) in 655, mitral valve replacement (MVR) in 1048 and combined AVR and MVR in 357 patients. From echocardiography database we found significantly higher incidence of PVL after combine AVR + MVR (n = 48; 13.45% than isolated MVR (n = 46; 4.38%) and AVR (n = 29; 4.43%). Mechanical valve was implanted in 82 cases and bioprosthesis in 41 cases. Initial VR was performed in 55% of patients (n = 68). First re-do has been done in 32 patients (26%), second-, third- and forth reoperation were performed in 11 (8.9%), 9 (7.3%) and 3 (2.4%) patients, respectively. Mild to moderate PVL was diagnosed in 90 cases (73%) and 33 (27%) patients had moderate to severe PVR according TTE. It was significantly higher percentage of moderate and severe PVR after MVR than AVR (p = 0.025). There was significantly higher incidence of reoperation in mitral then aortic position (p = 0.037). Conclusion: Paravalvular leakage after mitral valve replacement is severe and has a more detrimental clinical outcome compared to that after aortic valve replacement. Incidence of PVL is significantly higher after combine valve replacement than single valve replacement

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

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