Journal
ATHEROSCLEROSIS
Volume 277, Issue -, Pages 425-433Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2018.06.878
Keywords
Familial hypercholesterolemia; LDLR; LDLRAP1; Xanthomata; Next-generation sequencing; Missense variant; Coronary heart diseases
Funding
- National Science, Technology and Innovation Plan (MAAR-IFAH), Kingdom of Saudi Arabia [08-BIO34-10]
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Background and aims: Familial hypercholesterolemia (FH) is a predominantly autosomal dominant hereditary disorder with significant potential for expansion of coronary artery disease. Methods: To identify candidate variant/s in FH phenotype implicated genes, next-generation sequencing was performed using a targeted customized gene panel. Results: We recognized a 45-year-old Saudi female FH patient with double variants in the LDLR [c. 1255 T > G, p.(Y419D)] and LDLRAP1 genes [c. 604_605delTCinsA, p.(S202Tfs*2)]. The proband was found to be homozygous for the LDLR variant and heterozygous for the LDLRAP1 variant. Three of the proband's children were found to be double heterozygous for the LDLR/LDLRAP1 gene variant. While her other three children were heterozygous for the same single LDLR variant. Both variants were not previously reported. The variants segregation pattern correlated with the clinical picture and with the patient's lipid profile. FH severity was greater in the proband while her children did not show any clinical manifestations. The missense variant p.(Y419D) was found to be deleterious and clinically significant based on prediction identified by PolyPhen-2 and Proven. Molecular dynamics simulation was used to further analyze the effect of the variant p.(Y419D) on the structure and function of the LDLR protein. The secondary structure was investigated, as well as the solvent accessibility and stabilizing residues. The frameshift variant of the LDLRAP1 gene results in a truncated peptide that could affect the cellular internalization of LDLR/LDL complex. Conclusions: The finding of the combined variants in LDLR/LDLRAP1 genes triggering a severe FH phenotype is essential to elaborate the spectrum of variants causing FH and to understand the genotypephenotype correlation. (c) 2018 Elsevier B.V. All rights reserved.
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