Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.
Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.
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三名纯合子家族性高胆固醇血症患者：基因组测序和亲属分析。
DOI：
10.1002/mgg3.1007
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发表时间：
2019
影响因子：
2
通讯作者：
Pullinger,CliveR
中科院分区：
文献类型：
--
作者：
Wong,KarenHY;Levy-Sakin,Michal;Ma,Walfred;Gonzaludo,Nina;Mak,AngelCY;Vaka,Dedeepya;Poon,Annie;Chu,Catherine;Lao,Richard;Balamir,Melek;Grenville,Zoe;Wong,Nicolas;Kane,JohnP;Kwok,Pui-Yan;Malloy,MaryJ;Pullinger,CliveR
BackgroundHomozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low‐density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.ObjectiveWe aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.MethodsWe applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked‐Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR‐based screening assay was also established to detect theLDLRstructural variant in a cohort of 641 patients with elevated LDL.ResultsIn the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygousLDLRdamaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshiftLDLRvariant p.E113fs.ConclusionsWhile the application of WES can provide a cost‐effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of theLDLRexon 1 deletion highlights the broader utility of Linked‐Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.
