Targeted next-generation sequencing to diagnose disorders of HDL cholesterol

A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS. A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS. A low concentration of plasma HDL cholesterol (HDL-C) is one of the most common lipid abnormalities and an important risk factor for CVD. Low HDL-C predicts increased CVD risk, even among patients with aggressively treated LDL cholesterol (LDL-C) (1.Yusuf S. Hawken S. Ounpuu S. Dans T. Avezum A. Lanas F. McQueen M. Budaj A. Pais P. Varigos J. et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8412) Google Scholar, 2.Boekholdt S.M. Arsenault B.J. Hovingh G.K. Mora S. Pedersen T.R. Larosa J.C. Welch K.M. Amarenco P. Demicco D.A. Tonkin A.M. et al.Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.Circulation. 2013; 128: 1504-1512Crossref PubMed Scopus (147) Google Scholar, 3.Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1295) Google Scholar). HDL-C levels are highly heritable (4.Goode E.L. Cherny S.S. Christian J.C. Jarvik G.P. de Andrade M. Heritability of longitudinal measures of body mass index and lipid and lipoprotein levels in aging twins.Twin Res. Hum. Genet. 2007; 10: 703-711Crossref PubMed Scopus (60) Google Scholar) and display both locus and allelic heterogeneity, with multiple variants in several genes leading to very high or very low HDL-C. The genetic architecture of HDL-C is notable among polygenic traits in that rare variants with presumed large effect sizes are present in a substantial proportion of patients with very low or very high HDL-C, usually in the same genes that cause extremely rare Mendelian disorders of HDL-C (5.Cohen J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (901) Google Scholar, 6.Tietjen I. Hovingh G.K. Singaraja R. Radomski C. McEwen J. Chan E. Mattice M. Legendre A. Kastelein J.J. Hayden M.R. Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.Biochim. Biophys. Acta. 2012; 1821: 416-424Crossref PubMed Scopus (41) Google Scholar, 7.Frikke-Schmidt R. Nordestgaard B.G. Stene M.C. Sethi A.A. Remaley A.T. Schnohr P. Grande P. Tybjaerg-Hansen A. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.JAMA. 2008; 299: 2524-2532Crossref PubMed Scopus (393) Google Scholar, 8.Kiss R.S. Kavaslar N. Okuhira K. Freeman M.W. Walter S. Milne R.W. McPherson R. Marcel Y.L. Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1139-1145Crossref PubMed Scopus (52) Google Scholar, 9.Berge K.E. Leren T.P. Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol.Clin. Chim. Acta. 2010; 411: 2019-2023Crossref PubMed Scopus (15) Google Scholar, 10.Candini C. Schimmel A.W. Peter J. Bochem A.E. Holleboom A.G. Vergeer M. Dullaart R.P. Dallinga-Thie G.M. Hovingh G.K. Khoo K.L. et al.Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.Atherosclerosis. 2010; 213: 492-498Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 11.Alrasadi K. Ruel I.L. Marcil M. Genest J. Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.Atherosclerosis. 2006; 188: 281-291Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 12.Motazacker M.M. Peter J. Treskes M. Shoulders C.C. Kuivenhoven J.A. Hovingh G.K. Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels.Arte­rioscler. Thromb. Vasc. Biol. 2013; 33: 1521-1528Crossref PubMed Scopus (42) Google Scholar). This suggests that it may be possible to establish a molecular diagnosis in many patients with extreme HDL-C levels. However, detection of the specific molecular abnormality in patients with extreme HDL-C is rarely performed outside of specialized research laboratories because of the cost, complexity, and time required to do so, and uncertainty regarding the clinical utility of establishing a molecular diagnosis. The development of next-generation sequencing (NGS) technologies has created new opportunities for the routine use of sequencing in clinical medicine. Targeted NGS panels have been effectively used for newborn carrier screening and for the diagnosis of inherited cardiomyopathy, hereditary cancers, and other conditions (13.Rehm H.L. Disease-targeted sequencing: a cornerstone in the clinic.Nat. Rev. Genet. 2013; 14: 295-300Crossref PubMed Scopus (296) Google Scholar), but to date have not been established for disorders of HDL-C. The objective of this study was to evaluate the accuracy and diagnostic yield of a targeted NGS panel to establish the molecular diagnosis of abnormal HDL-C in a range of patients with extreme HDL phenotypes visiting a specialty lipid clinic. Our results indicate that this approach can reliably and accurately identify pathogenic variants in a substantial proportion of patients with low levels of HDL-C. We recruited consecutive patients with HDL-C levels below the 10th percentile or greater than the 90th percentile using age- and gender-adjusted population data from the S. The of plasma high-density lipoprotein cholesterol levels. The PubMed Scopus Google Scholar), to of other lipid from the a large specialty lipid a We not to patients with of low HDL-C or high HDL-C were not were not or were or to a patients in a molecular diagnosis of a Mendelian of HDL been established by Sanger sequencing C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar). data were from the medical multiple of were used the most subjects This study was by the of the of was isolated from using or using and using the assay were to the capture was performed with was by the and to a concentration of was performed on an in were to the using in and the by the for were using the We the and for by of of of and for and for variants and that were with the and and of variants and and We prioritized variants in HDL genes to the variants that are to be in the M. K. The Med. PubMed Scopus Google variants on of the intron/exon and that are novel or rare in and in study and novel or rare variants that were to be by all of and that were by Sanger sequencing of on ABCA1 were the and the and mutations by and in were C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar). efflux were C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar), in the of performed in were performed by the using of The and were time and was the of in the of and the of performed in are were with or for or or for were performed in was We a NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with in plasma lipid on data from the and of the We genes in rare variants are to cause highly penetrant effects on plasma levels of HDL-C, and lipoprotein on the to We a using to capture of genes of lipoprotein is from the Mendelian in in a new The is from the Mendelian in the accuracy and diagnostic yield of this sequenced 141 patients with extreme levels of HDL-C, including patients with extremely low HDL-C and patients with extremely high HDL-C. This population was to a substantial of variants in genes (5.Cohen J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (901) Google Scholar, S. Hawken S. Ounpuu S. Dans T. Avezum A. Lanas F. McQueen M. Budaj A. Pais P. Varigos J. et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8412) Google Scholar, 2.Boekholdt S.M. Arsenault B.J. Hovingh G.K. Mora S. Pedersen T.R. Larosa J.C. Welch K.M. Amarenco P. Demicco D.A. Tonkin A.M. et al.Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.Circulation. 2013; 128: 1504-1512Crossref PubMed Scopus (147) Google Scholar, 3.Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1295) Google Scholar, E.L. Cherny S.S. Christian J.C. Jarvik G.P. de Andrade M. Heritability of longitudinal measures of body mass index and lipid and lipoprotein levels in aging twins.Twin Res. Hum. Genet. 2007; 10: 703-711Crossref PubMed Scopus (60) Google Scholar, J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (901) Google Scholar, 6.Tietjen I. Hovingh G.K. Singaraja R. Radomski C. McEwen J. Chan E. Mattice M. Legendre A. Kastelein J.J. Hayden M.R. Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.Biochim. Biophys. Acta. 2012; 1821: 416-424Crossref PubMed Scopus (41) Google Scholar, 7.Frikke-Schmidt R. Nordestgaard B.G. Stene M.C. Sethi A.A. Remaley A.T. Schnohr P. Grande P. Tybjaerg-Hansen A. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.JAMA. 2008; 299: 2524-2532Crossref PubMed Scopus (393) Google Scholar, 8.Kiss R.S. Kavaslar N. Okuhira K. Freeman M.W. Walter S. Milne R.W. McPherson R. Marcel Y.L. Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1139-1145Crossref PubMed Scopus (52) Google Scholar, 9.Berge K.E. Leren T.P. Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol.Clin. Chim. Acta. 2010; 411: 2019-2023Crossref PubMed Scopus (15) Google Scholar, 10.Candini C. Schimmel A.W. Peter J. Bochem A.E. Holleboom A.G. Vergeer M. Dullaart R.P. Dallinga-Thie G.M. Hovingh G.K. Khoo K.L. et al.Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.Atherosclerosis. 2010; 213: 492-498Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 11.Alrasadi K. Ruel I.L. Marcil M. Genest J. Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.Atherosclerosis. 2006; 188: 281-291Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 12.Motazacker M.M. Peter J. Treskes M. Shoulders C.C. Kuivenhoven J.A. Hovingh G.K. Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels.Arte­rioscler. Thromb. Vasc. Biol. 2013; 33: 1521-1528Crossref PubMed Scopus (42) Google Scholar). The clinical of patients are in with low HDL-C plasma cholesterol and and a of with A. M. Chan J.J. Low of among patients with high levels of high-density lipoprotein 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). patients in both were of of patients with extreme HDL-C HDL-C coronary artery for of and for of in a new coronary artery for of and for of We performed sequencing of this to a of of were by or of targeted of with an of or The of with of with or was with for with of with or that with the capture of We identified variants that including variants, variants, variants, variants, variants of the and variants of We prioritized variants on established medical genetics S. S. M.R. E. of the for for and of Med. 2008; 10: Full Text Full Text PDF PubMed Scopus Google Scholar), to be for abnormalities of HDL-C in were or rare variants in and in study in genes were in a or or for variants, were to be by and variants in including variants in low HDL-C genes and variants in high HDL-C genes the 35 patients with prioritized variants, patients in the ABCA1 gene were most by variants in variants that were identified in or of the prioritized variants identified were including novel variants in ABCA1, novel variants in novel variants in of APOA1, and one novel in of and and probably pathogenic variants identified in patients with extreme HDL HDL is on with from and Functional on mutation in in to the was in a with low HDL-C, high HDL-C, or in both of in a new is on with from and Functional on mutation in in to the was in a with low HDL-C, high HDL-C, or in both of patients with extremely low HDL-C were to or mutations in the APOA1, ABCA1, and genes This a identification with extremely low HDL-C and to be for a novel in the gene a with HDL-C to be for one mutation in ABCA1 and one novel in ABCA1 and a with extremely low HDL-C and levels to be for a novel in for a identified in ABCA1 M.C. C. T. C. Dallinga-Thie G.M. J. C. et for functional and mutations in 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). results established molecular of the rare Mendelian disorders and in is the of and a in HDL-C was to be for the same establishing a for this with HDL-C with a new molecular diagnosis of HDL-C HDL-C in a new with extremely high HDL-C was for variants in and A. S. et the allelic the of rare and common variants to HDL Genet. PubMed Scopus Google Scholar). of with high HDL-C was for in a high that is present in of of but in of with low HDL-C was for both a novel in ABCA1 leading to and a novel mutation in This is with data that mutations in ABCA1 are to the effects of mutations in I. Bochem A.E. Singaraja Radomski C. Mattice M. Legendre A. Hovingh G.K. Kastelein J.J. et mutations in associated with high HDL cholesterol in Genet. PubMed Scopus Google Scholar). The of prioritized alleles in genes to cause low HDL-C was highly patients with low HDL-C, with of alleles in patients with low HDL-C and in patients with high HDL-C. of prioritized alleles in genes to cause high HDL-C were in patients with high HDL-C. patients with low HDL-C, of the prioritized alleles were in genes to cause low HDL-C, and were in genes to cause high HDL-C. suggest that were in variants with penetrant effects on the lipid phenotypes in A notable is the in pathogenic or probably pathogenic variants in with low HDL-C of low HDL-C and with high HDL-C of high HDL-C all in the that variants may not contribute to the in HDL-C in We performed Sanger sequencing of to the 35 prioritized variants, present of were confirmed by Sanger that the NGS assay with the We the of the NGS assay by of one in NGS was in We a molecular diagnosis to have been a a pathogenic or probably pathogenic in a gene to cause the present in that in a low HDL-C gene in a with low HDL-C and We variants in from this because of the that a proportion of patients with high low HDL-C variants in this Overall, a molecular diagnosis was established in of patients with low HDL-C and of patients with high HDL-C The of patients in a molecular diagnosis was not patients of with a molecular diagnosis with low HDL-C and with high that results were not by population the low HDL-C of HDL-C levels were among in a molecular diagnosis was with in molecular diagnosis was the low HDL-C patients in a molecular diagnosis was levels and a a of with in molecular diagnosis was among patients with high HDL-C, the HDL-C level not with or a molecular diagnosis the of assay to identified sequenced patients with rare mutations in the ABCA1 gene identified by Sanger sequencing C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar). This for mutations in ABCA1 and one for mutations in were identified by NGS. However, it is that one of to be pathogenic C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar), not have on from the intron/exon of the the functional of variants identified by performed functional validation of a subset of We the ABCA1 and variants, identified in and in variants levels of by and of by with We the of with variants to efflux cholesterol in to The of cholesterol efflux the an in efflux with ABCA1 that variants and loss-of-function results have been for mutation in ABCA1 that the same A. Hayden M.R. mutations in ABCA1 have effects on ABCA1 function and lipid phenotypes both in and in Res. 2006; PubMed Scopus Google Scholar). We in plasma from with variants in the gene with patients with and HDL-C levels. This the novel in one in the and in one in the We the and variants, both of have been to cause low HDL-C (5.Cohen J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (901) Google Scholar, Tybjaerg-Hansen A. A.A. J. Nordestgaard B.G. R. HDL cholesterol and ischemic cardiovascular a Mendelian study of HDL cholesterol in 2012; PubMed Scopus Google Scholar), but have not been We in patients and in one all in the to patients with and HDL-C for or variants in plasma with The for the for of with that was not than the data indicate that patients with variants in have plasma with the that variants loss-of-function We have a targeted NGS panel for molecular diagnosis of disorders of lipid We the of this panel in a population of patients with extreme HDL-C levels identified a of patients with rare mutations that HDL-C. The of this study that this panel is highly and has high to identify pathogenic and probably pathogenic variants that the of several novel variants in genes with associated clinical phenotypes and functional validation of a subset of and that a molecular diagnosis can be established in a substantial of patients with extremely low HDL-C visiting a specialty lipid clinic. Our results high accuracy of this assay to pathogenic is that assay accurately a pathogenic mutation in the ABCA1 gene C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar) with high levels of of the of this of the of an that it have been by most that identify variants or of the intron/exon This the of by We that the NGS assay identify the molecular of rare Mendelian disorders of HDL-C, and of patients the associated with conditions in disease or in This suggests that the approach may be to identify patients with rare Mendelian disorders of HDL-C with an approach on of have Sanger sequencing to identify pathogenic mutations in patients with Mendelian disorders of HDL-C C. J.A. F. S. J. et and molecular characterization of novel mutations in ABCA1 in with PubMed Scopus Google Scholar). large genes ABCA1 this approach is and of genes pathogenic mutation is identified in the the targeted of multiple and multiple genes in both the and time on a and study was to pathogenic variants, it is that 21 of the prioritized variants were confirmed of of variants by in or results the research and of targeted gene panels for both disease genes and important this a gene on the that patients with the have levels of plasma HDL-C C. S. E. lipid levels in patients with cholesterol Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. K.M. The of lipid and Res. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, Chan T. lipid efflux and in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Our results a proportion of patients with low high HDL-C variants in do not a for variants in this gene low HDL-C in the this not the of a pathogenic or probably pathogenic in to a molecular diagnosis of low HDL-C. sizes and functional may to the of rare variants in on HDL-C levels. study the use of a targeted NGS panel for lipid disorders in patients with abnormal or levels and in patients with and of the A. J. a next-generation clinical panel for Res. Full Text Full Text PDF PubMed Scopus Google Scholar). study a high level of accuracy in mutations The of by that assay was than was by assay to the capture of with results on disorders of and the high accuracy to identify pathogenic variants abnormalities of HDL-C, suggest that targeted NGS panels can accurately identify pathogenic variants the range of clinical We identified a pathogenic or probably pathogenic in 35.9% of patients with low HDL-C, a high diagnostic yield in this among patients with low HDL-C, the HDL-C level was among in a pathogenic was identified with in was identified This suggests that identification of a molecular in patients with low HDL-C may identify a extreme of and that the diagnostic yield be among patients with the levels of HDL-C. patients with an HDL-C of than or to or the molecular diagnosis have increased to or This that established HDL genes for the of of extremely low HDL-C, and that are to be genes this that to be The that patients with low HDL-C in pathogenic was identified levels and a a of is with the that the low HDL-C in patients may be to other than due to a genetic to the low HDL-C the diagnostic yield in patients with extremely high HDL-C was in that may be genetic or factors that this or that a greater proportion of patients have multiple variants in genes with effect sizes that may not have been by approach M.M. Peter J. Treskes M. Shoulders C.C. Kuivenhoven J.A. Hovingh G.K. Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels.Arte­rioscler. Thromb. Vasc. Biol. 2013; 33: 1521-1528Crossref PubMed Scopus (42) Google Scholar). are several of Our assay was to variants and or may not have been to and variants it is that detection of this of of the mutations in the ABCA1 are large or that the of pathogenic variants be by it is not possible to the of novel variants by This is the for variants, and it is that of the novel variants in study that were to be are in We used a by that all in that a novel was for to it probably the of to functional validation of a subset of novel variants that many of the variants in this study are the prioritized variants with the associated of prioritized alleles in low HDL genes were in patients with low HDL-C. of all rare variants in low HDL-C genes a of rare alleles in low HDL genes were in patients with low HDL-C. This that approach variants with penetrant effects on lipid a subset of the variants functional data is with the that many of the variants do the function of the not functional characterization of all novel variants This the of clinical in novel variants are but functional characterization may not be the molecular cause of HDL-C or other lipid or lipoprotein diagnostic and screening in the of patients with mutations of a molecular diagnostic has been to the use of R. I. Kastelein J.J. molecular diagnosis of on but a 2010; PubMed Scopus Google Scholar, J.C. Kastelein J.J. with genetic screening for Med. PubMed Scopus Google Scholar). identification of molecular abnormalities in patients with low HDL-C cardiovascular and and may with or targeted for specific disorders of HDL are in development Hovingh G.K. B.J. Holleboom A.G. from to J. Med. 2013; Google Scholar, of on and in with of 2012; Scholar), and the identification of specific molecular in patients with abnormal HDL-C levels may identify for have a novel targeted NGS panel for disorders of lipid Our validation study in patients with extreme levels of HDL-C that this assay is highly for the identification of pathogenic variants and that the diagnostic yield of an approach is among patients with very low HDL-C. Targeted sequencing the to diagnostic and may to new opportunities for and in patients with abnormalities of plasma lipid levels. The the patients in this with HDL cholesterol identification LDL cholesterol next-generation sequencing untranslated

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