Whole Exome Sequencing Reveals Multiple Mutations in Uncommon Genes of Familial Hypercholesterolaemia

Whole exome sequencing (WES) is an innovative, precise procedure established on the next generation sequencing and has rapidly become esteemed in medical genetics. We have used WES to study patient with suspected genetic conditions with no apparent recognizable familial hypercholesterolemia (FH). In the tested proband, multiple causative mutations were identified in LPL, EPHX2, PCSK9, APOB, ABCA1 and ABCG8 genes. The identified mutations in the LPL gene were heterozygous mutation [c.106G>A, p. (Asp36Asn)] in exon 2 and another heterozygous mutation [c.1421C>G, p.(Ser474*)] in exon 9. EPHX2 gene of the proband showed a novel heterozygous mutation [c.1644delC, p.(Pro549fs)] in exon 19. In addition, heterozygous mutations were identified in exon 1 of PCSK9 gene [c.158C>T, p.(Ala53Val)] and exon 4 of APOB [c.293C>T, p.(Thr98Ile)]. Likewise, homozygous mutations were found in exon 35 of ABCA1 gene [c.4760A>G, p.(Lys1587Arg)] and exon 13 of ABCG8 gene [c.1895T>C, p.(Val632Ala)], a common mutation highly associated with hypercholesterolemia based on the p-value by phenolyzer prioritization method. All causative mutations were validated by capillary sequencing method and confirmed the presence of homozygous and heterozygous mutations detected in the proband. All the causative mutations were functionally predicted to be deleterious including a novel frameshift and common missense mutation. Further investigations of the common mutation using Molecular dynamic (MD) simulation with solvated condition confirmed the functional and structural impact of the changes on the mutated proteins.