Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing
Abstract
:1. Introduction
2. Results
2.1. Clinically Diagnosed FH Subjects
2.2. Detection Rate and Prevalence of Genetically Confirmed FH in the Malaysian Community
2.3. Genotype Frequencies of FH Pathogenic Variants
2.4. Distribution of Identified Variants According to the Genes
2.5. List of Pathogenic Variants Identified amongst Genetically Confirmed FH Subjects
3. Discussion
4. Materials and Methods
4.1. Study Design and Populations
4.2. Research Ethics
4.3. Sample Collection
4.4. Targeted Next Generation Sequencing
4.5. Bioinformatics Analysis
4.6. Statisctical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
References
- Sun, D.; Zhou, B.-Y.; Li, S.; Sun, N.-L.; Hua, Q.; Wu, S.-L.; Cao, Y.-S.; Guo, Y.-L.; Wu, N.-Q.; Zhu, C.-G.; et al. Genetic basis of index patients with familial hypercholesterolemia in Chinese population: Mutation spectrum and genotype-phenotype correlation. Lipids Health Dis. 2018, 17, 252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bruikman, C.S.; Hovingh, G.K.; Kastelein, J.J. Molecular basis of familial hypercholesterolemia. Curr. Opin. Cardiol. 2017, 32, 262–266. [Google Scholar] [CrossRef] [PubMed]
- Miroshnikova, V.V.; Romanova, O.V.; Ivanova, O.N.; Fedyakov, M.A.; Panteleeva, A.A.; Barbitoff, Y.A.; Muzalevskaya, M.V.; Urazgildeeva, S.A.; Gurevich, V.S.; Urazov, S.P.; et al. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomed. Rep. 2020, 14, 15. [Google Scholar] [CrossRef] [PubMed]
- Sarraju, A.; Knowles, J.W. Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia. Front. Cardiovasc. Med. 2019, 6, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ajufo, E.; Cuchel, M. Improving the yield of genetic testing in familial hypercholesterolaemia. Eur. Heart J. 2017, 38, 574–576. [Google Scholar] [CrossRef] [Green Version]
- Gidding, S.S.; Champagne, M.A.; De Ferranti, S.D.; Defesche, J.; Ito, M.K.; Knowles, J.W.; McCrindle, B.; Raal, F.; Rader, D.; Santos, R.D.; et al. The Agenda for Familial Hypercholesterolemia. Circulation 2015, 132, 2167–2192. [Google Scholar] [CrossRef]
- Talmud, P.J.; Shah, S.; Whittall, R.; Futema, M.; Howard, P.; A Cooper, J.; Harrison, S.C.; Li, K.; Drenos, F.; Karpe, F.; et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: A case-control study. Lancet 2013, 381, 1293–1301. [Google Scholar] [CrossRef] [Green Version]
- Futema, M.; Shah, S.; A Cooper, J.; Li, K.; A Whittall, R.; Sharifi, M.; Goldberg, O.; Drogari, E.; Mollaki, V.; Wiegman, A.; et al. Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries. Clin. Chem. 2015, 61, 231–238. [Google Scholar] [CrossRef] [Green Version]
- IIacocca, M.A.; Hegele, R.A. Recent advances in genetic testing for familial hypercholesterolemia. Expert Rev. Mol. Diagn. 2017, 17, 641–651. [Google Scholar] [CrossRef]
- Tada, H.; Kawashiri, M.-A.; Nohara, A.; Inazu, A.; Kobayashi, J.; Mabuchi, H.; Yamagishi, M. Autosomal Recessive Hypercholesterolemia: A Mild Phenotype of Familial Hypercholesterolemia: Insight from the Kinetic Study using Stable Isotope and Animal Studies. J. Atheroscler. Thromb. 2015, 22, 1–9. [Google Scholar] [CrossRef]
- Abdul-Razak, S.; Rahmat, R.; Mohd Kasim, A.; Rahman, T.A.; Muid, S.; Nasir, N.M.; Ibrahim, Z.; Kasim, S.; Ismail, Z.; Abdul Ghani, R.; et al. Diagnostic performance of various familial hypercholesterolaemia diagnostic criteria compared to Dutch lipid clinic criteria in an Asian population. BMC Cardiovasc. Disord. 2017, 17, 264. [Google Scholar] [CrossRef] [Green Version]
- Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS): The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur. Heart J. 2020, 41, 111–188. [Google Scholar] [CrossRef] [Green Version]
- Pang, J.; Chan, D.C.; Hu, M.; Muir, L.A.; Kwok, S.; Charng, M.-J.; Florkowski, C.M.; George, P.M.; Lin, J.; Loi, D.D.; et al. Comparative aspects of the care of familial hypercholesterolemia in the “Ten Countries Study”. J. Clin. Lipidol. 2019, 13, 287–300. [Google Scholar] [CrossRef]
- Nawawi, H.; Chua, Y.-A.; Watts, G.F. The Brave New World of Genetic Testing in the Management of the Dyslipidaemias. Curr. Opin. Cardiol. 2020, 35, 226–233. [Google Scholar] [CrossRef]
- Hsiung, Y.-C.; Lin, P.-C.; Chen, C.-S.; Tung, Y.-C.; Yang, W.-S.; Chen, P.-L.; Su, T.-C. Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan. Atherosclerosis 2018, 277, 440–447. [Google Scholar] [CrossRef]
- Tromp, T.R.; Hartgers, M.L.; Hovingh, G.K.; Vallejo-Vaz, A.J.; Ray, K.K.; Soran, H.; Freiberger, T.; Bertolini, S.; Harada-Shiba, M.; Blom, D.J.; et al. Worldwide experience of homozygous familial hypercholesterolaemia: Retrospective cohort study. Lancet 2022, 399, 719–728. [Google Scholar] [CrossRef]
- Vallejo-Vaz, A.J.; De Marco, M.; Stevens, C.A.; Akram, A.; Freiberger, T.; Hovingh, G.K.; Kastelein, J.J.; Mata, P.; Raal, F.J.; Santos, R.D. Overview of the current status of familial hypercholesterolaemia care in over 60 countries—The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis 2018, 277, 234–255. [Google Scholar] [CrossRef] [Green Version]
- Moffa, S.; Mazzuccato, G.; De Bonis, M.; De Paolis, E.; Onori, M.E.; Pontecorvi, A.; Urbani, A.; Giaccari, A. Identification of Two Novel LDLR Variants by Next Generation Sequencing. Ann. Ist. Super. Sanita 2020, 56, 122–127. [Google Scholar] [CrossRef]
- Nordestgaard, B.G.; Benn, M. Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: Who does it in the world? Eur. Heart J. 2017, 38, 1580–1583. [Google Scholar] [CrossRef] [Green Version]
- Chua, Y.-A.; Razman, A.Z.; Ramli, A.S.; Kasim, N.A.M.; Nawawi, H.M. Familial Hypercholesterolaemia in the Malaysian Community: Prevalence, Under-Detection and Under-Treatment. J. Atheroscler. Thromb. 2021, 28, 1095–1107. [Google Scholar] [CrossRef]
- Alex, L.; Chahil, J.K.; Lye, S.H.; Bagali, P.; Ler, L.W. Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population. J. Hum. Genet. 2012, 57, 358–362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Al-Khateeb, A.; Al-Talib, H.; Mohamed, M.S.; Yusof, Z.; Zilfalil, B.A. Phenotype-genotype analyses of clinically diagnosed Malaysian familial hypercholestrolemic patients. Adv. Clin. Exp. Med. 2013, 22, 57–67. [Google Scholar] [PubMed]
- Vallejo-Vaz, A.J.; Ray, K.K. Epidemiology of Familial Hypercholesterolaemia: Community and Clinical. Atherosclerosis 2018, 277, 289–297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khoo, K.L.; Van Acker, P.; Defesche, J.C.; Tan, H.; Van De Kerkhof, L.; Eijk, S.J.H.-V.; Kastelein, J.J.; Deslypere, J.P. Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia. Clin. Genet. 2001, 58, 98–105. [Google Scholar] [CrossRef]
- Bertolini, S.; Pisciotta, L.; Rabacchi, C.; Cefalù, A.B.; Noto, D.; Fasano, T.; Signori, A.; Fresa, R. Spectrum of Mutations and Phenotypic Expression in Patients with Autosomal Dominant Hypercholesterolemia Identified in Italy. Atherosclerosis 2013, 227, 342–348. [Google Scholar] [CrossRef] [PubMed]
- Huijgen, R.; Vissers, M.N.; Kindt, I.; Trip, M.D.; de Groot, E.; Kastelein, J.J.P.; Hutten, B.A. Assessment of Carotid Atherosclerosis in Normocholesterolemic Individuals with Proven Mutations in the Low-Density Lipoprotein Receptor or Apolipoprotein B Genes. Circ. Cardiovasc. Genet. 2011, 4, 413–417. [Google Scholar] [CrossRef] [Green Version]
- Pek, S.L.T.; Dissanayake, S.; Fong, J.C.W.; Lin, M.X.; Chan, E.Z.L.; Tang, J.I.S.; Lee, C.W.; Ong, H.Y. Spectrum of Mutations in Index Patients with Familial Hypercholesterolemia in Singapore: Single Center Study. Atherosclerosis 2017, 269, 106–116. [Google Scholar] [CrossRef]
- Al-Khateeb, A.; Zahri, M.K.; Mohamed, M.S.; Sasongko, T.H.; Ibrahim, S.; Yusof, Z.; A Zilfalil, B. Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia. BMC Med. Genet. 2011, 12, 40. [Google Scholar] [CrossRef] [Green Version]
- Robles-Osorio, L.; Huerta-Zepeda, A.; Ordóñez, M.L.; Canizales-Quinteros, S.; Díaz-Villaseñor, A.; Gutiérrez-Aguilar, R.; Riba, L.; Huertas-Vázquez, A.; Rodríguez-Torres, M.; Gómez-Díaz, R.A.; et al. Genetic Heterogeneity of Autosomal Dominant Hypercholesterolemia in Mexico. Arch. Med Res. 2006, 37, 102–108. [Google Scholar] [CrossRef]
- Brænne, I.; Kleinecke, M.; Reiz, B.; Graf, E.; Strom, T.; Wieland, T.; Fischer, M.; Kessler, T. Systematic Analysis of Variants Related to Familial Hypercholesterolemia in Families with Premature Myocardial Infarction. Eur. J. Hum. Genet. 2016, 24, 191–197. [Google Scholar] [CrossRef]
- Chmara, M.; Wasag, B.; Zuk, M.; Kubalska, J.; Wegrzyn, A.; Bednarska-Makaruk, M.; Pronicka, E.; Wehr, H. Molecular Characterization of Polish Patients with Familial Hypercholesterolemia: Novel and Recurrent LDLR Mutations. J. Appl. Genet. 2010, 51, 95–106. [Google Scholar] [CrossRef] [PubMed]
- Lacaze, P.; Sebra, R.; Riaz, M.; Hooper, A.J.; Tiller, J.; Bakshi, A.; Woods, R.L.; Tonkin, A.M. Familial Hypercholesterolemia in a Healthy Elderly Population. Circ. Genom. Precis. Med. 2020, 13, e002938. [Google Scholar] [CrossRef] [PubMed]
- Meshkov, A.; Ershova, A.; Kiseleva, A.; Zotova, E.; Sotnikova, E.; Petukhova, A.; Zharikova, A.; Malyshev, P. The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. Genes 2021, 12, 66. [Google Scholar] [CrossRef] [PubMed]
- Azian, M.; Hapizah, M.N.; Khalid, B.A.; Khalid, Y.; Rosli, A.; Jamal, R.; Malays, J.P. Use of the Denaturing Gradient Gel Electrophoresis (DGGE) Method for Mutational Screening of Patients with Familial Hypercholesterolaemia (FH) and Familial Defective Apolipoprotein B100 (FDB). Malays J. Pathol. 2006, 28, 7–15. [Google Scholar] [PubMed]
- Bunn, C.F.; Lintott, C.J.; Scott, R.S.; George, P.M. Comparison of SSCP and DHPLC for the Detection of LDLR Mutations in a New Zealand Cohort. Hum. Mutat. 2002, 19, 311. [Google Scholar] [CrossRef]
- García-García, A.B.; Real, J.T.; Puig, O.; Cebolla, E.; Marín-García, P.; Martínez Ferrandis, J.I.; García-Sogo, M.; Civera, M. Molecular Genetics of Familial Hypercholesterolemia in Spain: Ten Novel LDLR Mutations and Population Analysis. Hum. Mutat. 2001, 18, 458–459. [Google Scholar] [CrossRef]
- Salazar, L.A.; Hirata, M.H.; Cavalli, S.A.; Nakandakare, E.R.; Forti, N.; Diament, J.; Giannini, S.D.; Bertolami, M.C. Molecular Basis of Familial Hypercholesterolemia in Brazil: Identification of Seven Novel LDLR Gene Mutations. Hum. Mutat. 2002, 19, 462–463. [Google Scholar] [CrossRef]
- Whittall, R.A.; Scartezini, M.; Li, K.; Hubbart, C.; Reiner, Z.; Abraha, A.; Neil, H.A.W.; Dedoussis, G. Development of a High-Resolution Melting Method for Mutation Detection in Familial Hypercholesterolaemia Patients. Ann. Clin. Biochem. 2010, 47 (Pt 1), 44–55. [Google Scholar] [CrossRef]
- Huijgen, R.; Kindt, I.; Fouchier, S.W.; Defesche, J.C.; Hutten, B.A.; Kastelein, J.J.P.; Vissers, M.N. Functionality of Sequence Variants in the Genes Coding for the Low-Density Lipoprotein Receptor and Apolipoprotein B in Individuals with Inherited Hypercholesterolemia. Hum. Mutat. 2010, 31, 752–760. [Google Scholar] [CrossRef] [Green Version]
- Abul-Husn, N.S.; Manickam, K.; Jones, L.K.; Wright, E.A.; Hartzel, D.N.; Gonzaga-Jauregui, C.; O’Dushlaine, C.; Leader, J.B. Genetic Identification of Familial Hypercholesterolemia within a Single, U.S. Health Care System. Science 2016, 354, aaf7000. [Google Scholar] [CrossRef]
- Vandrovcova, J.; Thomas, E.R.A.; Atanur, S.S.; Norsworthy, P.J.; Neuwirth, C.; Tan, Y.; Kasperaviciute, D.; Biggs, J. The Use of Next-Generation Sequencing in Clinical Diagnosis of Familial Hypercholesterolemia. Genet. Med. 2013, 15, 948–957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fouchier, S.W.; Defesche, J.C.; Umans-Eckenhausen, M.W.; Kastelein, J.P. The Molecular Basis of Familial Hypercholesterolemia in The Netherlands. Hum. Genet. 2001, 109, 602–615. [Google Scholar] [CrossRef]
- Sharifi, M.; Walus-Miarka, M.; Idzior-Waluś, B.; Malecki, M.T.; Sanak, M.; Whittall, R.; Li, K.W.; Futema, M. The Genetic Spectrum of Familial Hypercholesterolemia in South-Eastern Poland. Metabolism 2016, 65, 48–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, C.-C.; Niu, D.-M.; Charng, M.-J. Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. J. Atheroscler. Thromb. 2022, 29, 639–653. [Google Scholar] [CrossRef]
- Mohd Kasim, N.A.; Al-Khateeb, A.; Chua, Y.A.; Sanusi, A.R.; Mohd Nawawi, H. A Successful Pregnancy Outcome of Homozygous Familial Hypercholesterolaemia Patient on Statin Therapy. Malays. J. Pathol. 2021, 43, 87–93. [Google Scholar] [PubMed]
- Usifo, E.; Leigh, S.E.; Whittall, R.A.; Lench, N.; Taylor, A.; Yeats, C.; Orengo, C.A.; Martin, A.C.R. Low-Density Lipoprotein Receptor Gene Familial Hypercholesterolemia Variant Database: Update and Pathological Assessment. 2012, No. 1469-1809 (Electronic). Ann. Hum. Genet. 2012, 76, 387–401. [Google Scholar] [CrossRef] [PubMed]
- Chiou, K.-R.; Charng, M.-J. Genetic Diagnosis of Familial Hypercholesterolemia in Han Chinese. J. Clin. Lipidol. 2016, 10, 490–496. [Google Scholar] [CrossRef]
- Han, S.M.; Hwang, B.; Park, T.-G.; Kim, D.-I.; Rhee, M.-Y.; Lee, B.-K.; Ahn, Y.K.; Cho, B.R.; Woo, J.; Hur, S.-H.; et al. Genetic Testing of Korean Familial Hypercholesterolemia Using Whole-Exome Sequencing. PLoS ONE 2015, 10, e0126706. [Google Scholar] [CrossRef]
- Leren, T.P.; Berge, K.E. Identification of Mutations in the Apolipoprotein B-100 Gene and in the PCSK9 Gene as the Cause of Hypocholesterolemia. Clin. Chim. Acta. 2008, 397, 92–95. [Google Scholar] [CrossRef]
- Al-Khateeb, A.R.; Mohd, M.S.; Yusof, Z.; Zilfalil, B.A. Molecular Description of Familial Defective APOB-100 in Malaysia. Biochem. Genet. 2013, 51, 811–823. [Google Scholar] [CrossRef]
- Abifadel, M.; Guerin, M.; Benjannet, S.; Rabès, J.-P.; Le Goff, W.; Julia, Z.; Hamelin, J.; Carreau, V. Identification and Characterization of New Gain-of-Function Mutations in the PCSK9 Gene Responsible for Autosomal Dominant Hypercholesterolemia. Atherosclerosis 2012, 223, 394–400. [Google Scholar] [CrossRef] [PubMed]
- Seidah, N.G.; Abifadel, M.; Prost, S.; Boileau, C.; Prat, A. The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9. Pharmacol. Rev. 2017, 69, 33–52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hopkins, P.N.; Defesche, J.; Fouchier, S.W.; Bruckert, E.; Luc, G.; Cariou, B.; Sjouke, B.; Leren, T.P.; Harada-Shiba, M.; Mabuchi, H.; et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ. Cardiovasc. Genet. 2015, 8, 823–831. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Elbitar, S.; Susan-Resiga, D.; Ghaleb, Y.; El Khoury, P.; Peloso, G.; Stitziel, N.; Rabès, J.-P.; Carreau, V. New Sequencing Technologies Help Revealing Unexpected Mutations in Autosomal Dominant Hypercholesterolemia. Sci. Rep. 2018, 8, 1943. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garcia, C.K.; Wilund, K.; Arca, M.; Zuliani, G.; Fellin, R.; Maioli, M.; Calandra, S.; Bertolini, S.; Cossu, F.; Grishin, N.; et al. Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor Protein. Science 2001, 292, 1394–1398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eden, E.R.; Patel, D.D.; Sun, X.-M.; Burden, J.J.; Themis, M.; Edwards, M.; Lee, P.; Neuwirth, C. Restoration of LDL Receptor Function in Cells from Patients with Autosomal Recessive Hypercholesterolemia by Retroviral Expression of ARH1. J. Clin. Investig. 2002, 110, 1695–1702. [Google Scholar] [CrossRef]
- Santos, R.D. Advancing Prediction of Pathogenicity of Familial Hypercholesterolemia LDL Receptor Commonest Variants With Machine Learning Models. JACC Basic Transl. Sci. 2021, 6, 828–830. [Google Scholar] [CrossRef]
- Miyake, Y.; Yamamura, T.; Sakai, N.; Miyata, T.; Kokubo, Y.; Yamamoto, A. Update of Japanese Common <em>LDLR</Em> Gene Mutations and Their Phenotypes: Mild Type Mutation L547V Might Predominate in the Japanese Population. Atherosclerosis 2009, 203, 153–160. [Google Scholar] [CrossRef]
- Chiou, K.-R.; Charng, M.-J. Detection of Mutations and Large Rearrangements of the Low-Density Lipoprotein Receptor Gene in Taiwanese Patients With Familial Hypercholesterolemia. Am. J. Cardiol. 2010, 105, 1752–1758. [Google Scholar] [CrossRef]
- Setia, N.; Movva, S.; Balakrishnan, P.; Biji, I.K.; Sawhney, J.P.S.; Puri, R.; Arora, A.; Puri, R.D. Genetic Analysis of Familial Hypercholesterolemia in Asian Indians: A Single-Center Study. J. Clin. Lipidol. 2020, 14, 35–45. [Google Scholar] [CrossRef]
- Humphries, S.E.; Whittall, R.A.; Hubbart, C.S.; Maplebeck, S.; Cooper, J.A.; Soutar, A.K.; Naoumova, R.; Thompson, G.R. Genetic Causes of Familial Hypercholesterolaemia in Patients in the UK: Relation to Plasma Lipid Levels and Coronary Heart Disease Risk. J. Med. Genet. 2006, 43, 943–949. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Radovica-Spalvina, I.; Latkovskis, G.; Silamikelis, I.; Fridmanis, D.; Elbere, I.; Ventins, K.; Ozola, G.; Erglis, A. Next-Generation-Sequencing-Based Identification of Familial Hypercholesterolemia-Related Mutations in Subjects with Increased LDL-C Levels in a Latvian Population. BMC Med. Genet. 2015, 16, 86. [Google Scholar] [CrossRef] [Green Version]
- Maglio, C.; Mancina, R.M.; Motta, B.M.; Stef, M.; Pirazzi, C.; Palacios, L.; Askaryar, N.; Borén, J. Genetic Diagnosis of Familial Hypercholesterolaemia by Targeted Next-Generation Sequencing. J. Intern. Med. 2014, 276, 396–403. [Google Scholar] [CrossRef] [PubMed]
- Vallejo-Vaz, A.J.; Stevens, C.A.T.; Lyons, A.R.M.; Dharmayat, K.I.; Freiberger, T.; Hovingh, G.K.; Mata, P.; Raal, F.J. Global Perspective of Familial Hypercholesterolaemia: A Cross-Sectional Study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet 2021, 398, 1713–1725. [Google Scholar] [CrossRef] [PubMed]
- Hu, P.; Dharmayat, K.I.; Stevens, C.A.T.; Sharabiani, M.T.A.; Jones, R.S.; Watts, G.F.; Genest, J.; Ray, K.K. Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease. Circulation 2020, 141, 1742–1759. [Google Scholar] [CrossRef] [PubMed]
- Ershova, A.I.; Meshkov, A.N.; Bazhan, S.S.; Storozhok, M.A.; Efanov, A.Y.; Medvedeva, I.V.; Indukaeva, E.V.; Danilchenko, Y.V.; Kuzmina, O.K.; Barbarash, O.L.; et al. The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: A substudy of the ESSE-RF. PLOS ONE 2017, 12, e0181148. [Google Scholar] [CrossRef] [Green Version]
- Futema, M.; Cooper, J.A.; Charakida, M.; Boustred, C.; Sattar, N.; Deanfield, J.; Lawlor, D.A.; Timpson, N.J. Screening for Familial Hypercholesterolaemia in Childhood: Avon Longitudinal Study of Parents and Children (ALSPAC). Atherosclerosis 2017, 260, 47–55. [Google Scholar] [CrossRef] [Green Version]
- Ohta, T.; Kiwaki, K.; Endo, F.; Umehashi, H.; Matsuda, I. Dyslipidemia in Young Japanese Children: Its Relation to Familial Hypercholesterolemiaand Familial Combined Hyperlipidemia. Pediatr. Int. 2002, 44, 602–607. [Google Scholar] [CrossRef]
- Beheshti, S.; Madsen, C.M.; Varbo, A.; Benn, M.; Nordestgaard, B.G. Relationship of Familial Hypercholesterolemia and High Low-Density Lipoprotein Cholesterol to Ischemic Stroke: Copenhagen General Population Study. Circulation 2018, 138, 578–589. [Google Scholar] [CrossRef]
- Lahtinen, A.M.; Havulinna, A.S.; Jula, A.; Salomaa, V.; Kontula, K.; Besseling, J.; Kindt, I.; Hof, M. Prevalence and Clinical Correlates of Familial Hypercholesterolemia Founder Mutations in the General Population. Atherosclerosis 2015, 238, 64–69. [Google Scholar] [CrossRef]
- Miserez, A.R.; Martin, F.J.; Spirk, D. DIAgnosis and Management Of Familial Hypercholesterolemia in a Nationwide Design (DIAMOND-FH): Prevalence in Switzerland, Clinical Characteristics and the Diagnostic Value of Clinical Scores. Atherosclerosis 2018, 277, 282–288. [Google Scholar] [CrossRef] [PubMed]
- Reeskamp, L.F.; Hartgers, M.L.; Peter, J.; Dallinga-Thie, G.M.; Zuurbier, L.; Defesche, J.C.; Grefhorst, A.; Hovingh, G.K. A Deep Intronic Variant in LDLR in Familial Hypercholesterolemia. Circ. Genomic Precis. Med. 2018, 11, e002385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Langsted, A.; Kamstrup, P.R.; Benn, M.; Tybjærg-Hansen, A.; Nordestgaard, B.G. Lipoprotein(a) and Familial Hypercholesterolaemia–Authors’ Reply. Lancet Diabetes Endocrinol. 2016, 4, 730–731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ellis, K.L.; Pang, J.; Chan, D.C.; Hooper, A.J.; Bell, D.A.; Burnett, J.R.; Watts, G.F. Familial Combined Hyperlipidemia and Hyperlipoprotein(a) as Phenotypic Mimics of Familial Hypercholesterolemia: Frequencies, Associations and Predictions. J. Clin. Lipidol. 2016, 10, 1329–1337. [Google Scholar] [CrossRef]
- Wang, J.; Dron, J.S.; Ban, M.R.; Robinson, J.F.; McIntyre, A.D.; Alazzam, M.; Zhao, P.J.; Dilliott, A.A. Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 2439–2445. [Google Scholar] [CrossRef] [Green Version]
- Ito, M.K.; Watts, G.F. Challenges in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia. Drugs 2015, 75, 1715–1724. [Google Scholar] [CrossRef] [Green Version]
- Horton, J.D.; Cohen, J.C.; Hobbs, H.H. PCSK9: A Convertase That Coordinates LDL Catabolism. J. Lipid Res. 2009, 50 Suppl (Suppl), S172–S177. [Google Scholar] [CrossRef] [Green Version]
- Vergotine, J.; Thiart, R.; Kotze, M.J. Clinical versus Molecular Diagnosis of Heterozygous Familial Hypercholesterolaemia in the Diverse South African Population. S. Afr. Med. J. 2001, 91, 1053–1059. [Google Scholar]
- Minicocci, I.; Pozzessere, S.; Prisco, C.; Montali, A.; di Costanzo, A.; Martino, E.; Martino, F.; Arca, M. Analysis of Children and Adolescents with Familial Hypercholesterolemia. J. Pediatr. 2017, 183, 100–107. [Google Scholar] [CrossRef]
- Lima-Martínez, M.M.; Paoli, M.; Vázquez-Cárdenas, A.; Magaña-Torres, M.T.; Guevara, O.; Muñoz, M.C.; Parrilla-Alvarez, A.; Márquez, Y. Frequency and Clinical and Molecular Aspects of Familial Hypercholesterolemia in an Endocrinology Unit in Ciudad Bolívar, Venezuela. Endocrinol. diabetes y Nutr. 2017, 64, 432–439. [Google Scholar] [CrossRef]
- Bourbon, M.; Alves, A.C.; Medeiros, A.; da Silva, S.P.; Soutar, A. Familial hypercholesterolaemia in Portugal. Atherosclerosis 2008, 196, 633–642. [Google Scholar] [CrossRef] [PubMed]
- Graça, R.; Alves, A.C.; Zimon, M.; Pepperkok, R.; Bourbon, M. Functional Profiling of LDLR Variants: Important Evidence for Variant Classification: Functional Profiling of LDLR Variants. J. Clin. Lipidol. 2022. [Google Scholar] [CrossRef] [PubMed]
- Webb, J.; Sun, X.; Patel, D.; McCarthy, S.; Knight, B.; Soutar, A. Characterization of two new point mutations in the low density lipoprotein receptor genes of an English patient with homozygous familial hypercholesterolemia. J. Lipid Res. 1992, 33, 689–698. [Google Scholar] [CrossRef] [PubMed]
- Hobbs, H.H.; Brown, M.S.; Goldstein, J.L. Molecular Genetics of the LDL Receptor Gene in Familial Hypercholesterolemia. Hum. Mutat. 1992, 1, 445–466. [Google Scholar] [CrossRef] [PubMed]
- Thormaehlen, A.S.; Schuberth, C.; Won, H.-H.; Blattmann, P.; Joggerst-Thomalla, B.; Theiss, S.; Asselta, R.; Duga, S.; Merlini, P.A.; Ardissino, D.; et al. Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction. PLoS Genet. 2015, 11, e1004855. [Google Scholar] [CrossRef] [Green Version]
- Futema, M.; Whittall, R.A.; Kiley, A.; Steel, L.K.; Cooper, J.A.; Badmus, E.; Leigh, S.E.; Karpe, F. Analysis of the Frequency and Spectrum of Mutations Recognised to Cause Familial Hypercholesterolaemia in Routine Clinical Practice in a UK Specialist Hospital Lipid Clinic. Atherosclerosis 2013, 229, 161–168. [Google Scholar] [CrossRef]
- Holla, O.L.; Nakken, S.; Mattingsdal, M.; Ranheim, T.; Berge, K.E.; Defesche, J.C.; Leren, T.P. Effects of Intronic Mutations in the LDLR Gene on Pre-MRNA Splicing: Comparison of Wet-Lab and Bioinformatics Analyses. Mol. Genet. Metab. 2009, 96, 245–252. [Google Scholar] [CrossRef]
- Zhang, X.; Liu, Q.; Zhang, H.; Tan, C.; Zhu, Q.; Chen, S.; Du, Y.; Yang, H. Hyperlipidemia Patients Carrying LDLR Splicing Mutation c.1187-2A>G Respond Favorably to Rosuvastatin and PCSK9 Inhibitor Evolocumab. Mol. Genet. Genomics 2022, 297, 833–841. [Google Scholar] [CrossRef]
- Yang, K.-C.; Su, Y.-N.; Shew, J.-Y.; Tseng, W.-K.; Wu, C.-C.; Lee, Y.-T. LDLR and ApoB are Major Genetic Causes of Autosomal Dominant Hypercholesterolemia in a Taiwanese Population. J. Formos. Med. Assoc. 2007, 106, 799–807. [Google Scholar] [CrossRef] [Green Version]
- Jensen, H.K. The Molecular Genetic Basis and Diagnosis of Familial Hypercholesterolemia in Denmark. Dan. Med. Bull. 2002, 49, 318–345. [Google Scholar] [PubMed]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Anesthesia Analg. 2015, 17, 405–424. [Google Scholar] [CrossRef]
- Kim, H.N.; Kweon, S.-S.; Shin, M.-H. Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts. Chonnam Med. J. 2018, 54, 31–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xiang, R.; Fan, L.-L.; Lin, M.-J.; Li, J.-J.; Shi, X.-Y.; Jin, J.-Y.; Liu, Y.-X.; Chen, Y.-Q. The Genetic Spectrum of Familial Hypercholesterolemia in the Central South Region of China. Atherosclerosis 2017, 258, 84–88. [Google Scholar] [CrossRef] [PubMed]
- Chiou, K.-R.; Charng, M.-J. Common Mutations of Familial Hypercholesterolemia Patients in Taiwan: Characteristics and Implications of Migrations from Southeast China. Gene 2012, 498, 100–106. [Google Scholar] [CrossRef] [PubMed]
- Wald, D.S.; Bestwick, J.P.; Morris, J.K.; Whyte, K.; Jenkins, L.; Wald, N.J. Child–Parent Familial Hypercholesterolemia Screening in Primary Care. N. Engl. J. Med. 2016, 375, 1628–1637. [Google Scholar] [CrossRef]
- Fisher, E.; Scharnagl, H.; Hoffmann, M.M.; Kusterer, K.; Wittmann, D.; Wieland, H.; Gross, W.; März, W. Mutations in the Apolipoprotein (Apo) B-100 Receptor-Binding Region: Detection of Apo B-100 (Arg3500-->Trp) Associated with Two New Haplotypes and Evidence That Apo B-100 (Glu3405-->Gln) Diminishes Receptor-Mediated Uptake of LDL. Clin. Chem. 1999, 45, 1026–1038. [Google Scholar] [CrossRef] [PubMed]
- Nozue, T. Lipid Lowering Therapy and Circulating PCSK9 Concentration. J. Atheroscler. Thromb. 2017, 24, 895–907. [Google Scholar] [CrossRef] [Green Version]
- Sánchez-Hernández, R.M.; Di Taranto, M.D.; Benito-Vicente, A.; Uribe, K.B.; Lamiquiz-Moneo, I.; Larrea-Sebal, A.; Jebari, S.; Galicia-Garcia, U. The Arg499His Gain-of-Function Mutation in the C-Terminal Domain of <em>PCSK9</Em>. Atherosclerosis 2019, 289, 162–172. [Google Scholar] [CrossRef]
- Dron, J.S.; Hegele, R.A. Complexity of Mechanisms among Human Proprotein Convertase Subtilisin-Kexin Type 9 Variants. Curr. Opin. Lipidol. 2017, 28, 161–169. [Google Scholar] [CrossRef]
- Kosmas, C. Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial Hypercholesterolemia. Biomed. J. Sci. Tech. Res. 2017, 1. [Google Scholar] [CrossRef] [Green Version]
- Cui, Y.; Li, S.; Zhang, F.; Song, J.; Lee, C.; Wu, M.; Chen, H. Prevalence of Familial Hypercholesterolemia in Patients with Premature Myocardial Infarction. Clin. Cardiol. 2019, 42, 385–390. [Google Scholar] [CrossRef] [PubMed]
- Khera, A.V.; Hegele, R.A. What Is Familial Hypercholesterolemia, and Why Does It Matter? Circulation 2020, 141, 1760–1763. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, M.-A.; Nohara, A.; Inazu, A.; Mabuchi, H.; Yamagishi, M. Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia. Eur. Hear. J. 2017, 38, 1573–1579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Firus Khan, A.Y.; Ramli, A.S.; Abdul Razak, S.; Mohd Kasim, N.A.; Chua, Y.-A.; Ul-Saufie, A.Z.; Jalaludin, M.A.; Nawawi, H. The Malaysian HEalth and WellBeing AssessmenT (MyHEBAT) Study Protocol: An Initiation of a National Registry for Extended Cardiovascular Risk Evaluation in the Community. Int. J. Environ. Res. Public Heal. 2022, 19, 11789. [Google Scholar] [CrossRef] [PubMed]
- Civeira, F. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004, 173, 55–68. [Google Scholar] [CrossRef] [PubMed]
- Friedewald, W.T.; Levy, R.I.; Fredrickson, D.S. Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clin. Chem. 1972, 18, 499–502. [Google Scholar] [CrossRef] [PubMed]
Demographic Characteristics | Potential FH (N = 58) | Possible FH (N = 314) | p-Value |
---|---|---|---|
Age (years), mean ± SD | 58.9 ± 9.9 | 49.6 ± 13.1 | 0.01 * |
Gender, n (%) | |||
Males | 26 (44.8) | 145 (46.2) | NS |
Females | 32 (55.2) | 169 (53.8) | |
BMI (kg/m2), mean ± SD | 26.7 ± 5.8 | 27.6 ± 4.9 | NS |
Overweight and obesity | 43 (74.1) | 254 (80.1) | 0.042 |
Waist circumference (cm), mean ± SD | 89.2 ± 13.2 | 90.6 ± 11.2 | NS |
Hip circumference (cm), mean ± SD | 100.7 ± 11.9 | 101.7 ± 10.3 | NS |
Abdominal obesity (Male ≥ 0.90; female ≥ 0.85) | 37 (63.8) | 217 (69.1) | NS |
Comorbidities, n (%) | |||
Diabetes, n (%) | 11 (19.0) | 37 (11.8) | NS |
FPG (mmol/L), mean ± SD | 6.1 ± 2.7 | 6.0 ± 3.0 | NS |
RPG (mmol/L), mean ± SD | 6.6 ± 2.2 | 6.7 ± 3.8 | NS |
Hypertension, n (%) | 29 (50.0) | 141 (44.9) | NS |
SBP (mm/Hg), mean ± SD | 131.1 ± 18.6 | 132.0 ± 20.7 | NS |
DBP (mm/Hg), mean ± SD | 76.9 ± 10.9 | 80.5 ± 12.0 | NS |
Existing personal CVD (%) | 8 (13.8) | 16 (5.1) | 0.01 * |
Family history of PCAD, n (%) | 20 (34.5) | 42 (13.4) | 0.001 * |
Xanthomata, n (%) | 6 (10.3) | 0 (0.0) | 0.001 * |
Corneal arcus, n (%) | 44 (75.9) | 7 (2.2) | <0.001 * |
Lipid profiles, mean ± SD | |||
TC (mmol/L) | 7.4 ± 1.6 | 7.3 ± 1.0 | 0.001 * |
TG (mmol/L) | 1.8 ± 0.7 | 1.9 ± 0.7 | NS |
Baseline LDL-C (mmol/L) | 6.1 ± 1.4 | 5.6 ± 0.7 | <0.001 * |
HDL-C (mmol/L) | 1.4 ± 0.4 | 1.3 ± 0.3 | NS |
Category | Total FH Individuals (n = 372) | Potential FH Individuals (n = 58) | Possible FH Individuals (n = 314) |
---|---|---|---|
Presence of pathogenic variants in FH genes (LDLR, APOB, PCSK9) | 82/372 (22.0%) | 12/58 (20.7%) | 70/314 (22.3%) |
Absence of pathogenic variants in FH genes | 290/372 (78.0%) | 46/58 (79.3%) | 244/314 (77.7%) |
Clinically Diagnosed FH Subjects | Clinical Prevalence | Individuals with ≥1 PV in FH Genes | Genetically Confirmed Prevalence |
---|---|---|---|
Potential FH only | 58/5130 (1.1%–1:88) | 12/5130 (0.2%) | 1:427 |
Possible FH only | 314/5130 (6.1%–1:16) | 70/5130 (1.4%) | 1:73 |
All FH categories(Potential and Possible FH) | 372/5130 (7.3%–1:14) | 82/5130 (1.6%) | 1:63 |
Genotypes | Total Number of Individuals with PV (n = 82) | Percentage (%) |
---|---|---|
LDLR heterozygote | 26 | 31.7 |
APOB heterozygote | 18 | 22.0 |
PCSK9 heterozygote | 32 | 39.0 |
LDLR + APOB double heterozygous | 3 | 3.7 |
LDLR + PCSK9 double heterozygous | 1 | 1.2 |
APOB + PCSK9 double heterozygous | 2 | 2.4 |
82/82 | 100% |
Genes | PV (%) | VUS (%) |
---|---|---|
LDLR | 18/40 (45.0) | 13/71 (18.3) |
APOB | 15/40(37.5) | 42/71 (59.2) |
PCSK9 | 5/40 (12.5) | 12/71 (16.9) |
LDLRAP1 | 2/40 (5.0) | 4/71 (5.6) |
Total | 40 (100) | 71 (100) |
Variant | Database | In Silico Predicted Effects | ACMG | References | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
No. | HGVS | Exon/Intron | Individuals | dbSNP | LOVD | ClinVar | PolyPhen | SIFT | REVEL | ||
LDLR nonsynonymous variants | |||||||||||
1 | c.241C>T (R81C) | 3 | 1 | rs730882078 | LP, P | Conflicting (P,LP,VUS) | probably damaging | Deleterious | Likely disease causing | PV (PM1, PM2, PP2, PP3, PP4, PP5) | [25,26,27] |
2 | c.301G>A (E101K) | 3 | 4 | rs144172724 | LP, P | LP, P | probably damaging | Deleterious | Likely disease causing | PV (PS3, PM1, PM2, PP2,PP3, PP4, PP5) | [28,29] |
3 | c.580A>G (S194G) | 4 | 1 | rs373488885 | NR | VUS | benign | Tolerated | Likely benign | LP (PM1, PM2, PP2, PP4) | - |
4 | c.811G>A (V271I) | 5 | 1 | rs749220643 | VUS | Conflicting (LP,LB) | benign | Tolerated | Likely benign | LP (PM1, PM2, PP2, PP4, PP5) | [30] |
5 | c.833G>A (G278E) | 6 | 1 | - | NR | NR | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4) | - |
6 | c.949G>A (E317K) | 7 | 2 | rs746834464 | LP, P | Conflicting (P,LP,VUS) | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4, PP5) | [31,32,33] |
7 | c.1234A>C (M412L) | 9 | 1 | rs1225797407 | NR | P | benign | Tolerated | Likely benign | LP (PM1, PM2, PP2, PP4, PP5) | - |
8 | c.1284C>G (N428K) | 9 | 4 | rs368708058 | P, VUS | CF (LP,VUS) | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4, PP5) | [34,35,36] |
9 | c.1289T>G (V430G) | 9 | 1 | - | NR | NR | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PM5, PP2, PP3, PP4) | - |
10 | c.1571T>G (V524G) | 10 | 1 | - | LP | LP | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4, PP5) | [37,38] |
11 | c.1774G>T (G592W) | 12 | 6 | - | NR | NR | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PM5, PP2, PP3, PP4) | - |
12 | c.1820A>G (H607R) | 12 | 1 | rs879255033 | LP | LP | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4, PP5) | [39] |
13 | c.2383C>G (P795A) | 16 | 1 | - | NR | NR | probably damaging | Deleterious | Likely disease causing | LP (PM2, PM5, PP2, PP3, PP4) | - |
14 | c.2530G>A (G844S) | 17 | 1 | rs1555809614 | NR | P | probably damaging | Deleterious | Likely disease causing | LP (PM2, PP2, PP3, PP4, PP5) | - |
15 | c.1217G>A (R406Q) | 9 | 1 | rs552422789 | LP | LP | probably damaging | Deleterious | Likely disease causing | LP (PM1, PM2, PP2, PP3, PP4, PP5) | [27,40,41] |
16 | c.1246C>T (R416W) | 9 | 1 | rs570942190 | LP, P | LP, P | probably damaging | Deleterious | Likely disease causing | PV (PS3, PM1, PM2, PP2, PP3, PP4, PP5) | [25,42,43] |
17 | c.1867A>G (I623V) | 13 | 2 | rs555292896 | LB | Conflicting (P,VUS,B,LB) | benign | Tolerated | Likely disease causing | LP (PM1, PM2, PP2, PP4) | [44] |
LDLR splice site variant | |||||||||||
18 | c.1187-2A>G | 8 | 1 | rs879254823 | LP, P | LP, P | NA | NA | NA | PV (PVS1, PM1, PM2, PP4, PP5) | [45,46] |
No. | HGVS | Exon/ Intron | Individuals | dbSNP | LOVD | ClinVar | PolyPhen | SIFT | REVEL | ACMG | References |
APOB nonsynonymous variants | |||||||||||
1 | c.11303T>C (I3768T) | 26 | 2 | rs376825639 | VUS, P | VUS | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP4, PP5) | - |
2 | c.11006T>G (L3669R) | 26 | 1 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PM5, PP3, PP4) | - |
3 | c.9533A>C (K3178T) | 26 | 1 | - | NR | NR | possibly damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
4 | c.9107C>A (S3036Y) | 26 | 2 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
5 | c.8287A>C (K2763Q) | 26 | 1 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
6 | c.7975C>T (P2659S) | 26 | 1 | - | NR | NR | possibly damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
7 | c.7828G>C (A2610P) | 26 | 1 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
8 | c.5756T>C (L1919P) | 26 | 1 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
9 | c.4951G>A (G1651R) | 26 | 2 | rs748424949 | VUS | NR | possibly damaging | Deleterious | Likely benign | LP (PM1, PM2, PP1, PP3, PP4) | - |
10 | c.4867G>A (G1623S) | 26 | 1 | - | VUS | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
11 | c.1400C>G (A467G) | 11 | 3 | rs376602710 | LB | VUS | probably damaging | Deleterious | Likely disease causing | LP (PM2, PP3, PP4, PP5) | - |
12 | c.10579C>T (R3527W) | 26 | 1 | rs144467873 | P | Conflicting | probably damaging | Deleterious | Likely disease causing | PV (PS3, PM1, PM2, PP3, PP4) | [25,47,48] |
13 | c.8462C>T (P2821L) | 26 | 2 | rs72653095 | B, VUS | Conflicting | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | [49] |
14 | c.7619G>T (G2540V) | 26 | 1 | rs571626569 | B | Conflicting | possibly damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
APOB frameshift variant | |||||||||||
15 | c.13028_13029del (Y4343) | 29 | 4 | rs760832994 | NR | CF (LP, VUS) | NA | NA | NA | PV (PVS1, PS4, PM1, PM2, PP4, PP5) | [50] |
No. | HGVS | Exon/ Intron | Individuals | dbSNP | LOVD | ClinVar | PolyPhen | SIFT | REVEL | ACMG | References |
PCSK9 nonsynonymous variants | |||||||||||
1 | c.323T>G (L108R) (GOF) | 2 | 1 | - | NR | LP, P | probably damaging | Deleterious | Likely benign | PV (PS3, PM1, PM2, PP3, PP4, PP5) | [51] |
2 | c.1493A>C (E498A) | 9 | 31 | - | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM1, PM2, PP3, PP4) | - |
3 | c.1495C>G (R499G) | 9 | 4 | - | NR | NR | possibly damaging | Tolerated | Likely benign | LP (PM1, PM2, PM5, PP4) | - |
4 | c.212C>T (P71L) (GOF) | 2 | 2 | rs569379713 | LP | VUS | benign | Deleterious | Likely benign | LP (PM1, PM2, PP4, PP5) | [52,53] |
5 | c.286C>T (R96C) (GOF) | 2 | 1 | rs185392267 | VUS | Conflicting | probably damaging | Deleterious | Likely benign | PV (PS3, PM1, PM2, PP3, PP4, PP5) | [53,54] |
LDLRAP1 nonsynonymous variants * | |||||||||||
1 | c.281C>A (P94Q) | 3 | 2 | -. | NR | NR | probably damaging | Deleterious | Likely benign | LP (PM2, PM3, PP3, PP4) | - |
LDLRAP1 frameshift variants * | |||||||||||
No. | HGVS | Exon/ Intron | Individuals | dbSNP | LOVD | ClinVar | PolyPhen | SIFT | REVEL | ACMG | References |
2 | c.604delT | 6 | 1 | - | NR | P | NA | NA | NA | PV (PVS1, PM1, PM2, PM3, PP5) | [55,56] |
Country | Data Source | Prevalence | Reference |
---|---|---|---|
United Kingdom | Population-based | 1:252 | [67] |
United States | Genomic sequencing and HER data | 1:222 | [40] |
Japan | Children screening program | 1:617 | [68] |
Denmark | Population-based | 1:575 | [69] |
Finland | National FINRISK Study and the Health 2000 Cohort Studies | 1:813 | [70] |
Switzerland | Population-based | 1:549 | [71] |
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Razman, A.Z.; Chua, Y.-A.; Mohd Kasim, N.A.; Al-Khateeb, A.; Sheikh Abdul Kadir, S.H.; Jusoh, S.A.; Nawawi, H., on behalf of the MyHEBAT-FH Study Investigators. Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing. Int. J. Mol. Sci. 2022, 23, 14971. https://doi.org/10.3390/ijms232314971
Razman AZ, Chua Y-A, Mohd Kasim NA, Al-Khateeb A, Sheikh Abdul Kadir SH, Jusoh SA, Nawawi H on behalf of the MyHEBAT-FH Study Investigators. Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing. International Journal of Molecular Sciences. 2022; 23(23):14971. https://doi.org/10.3390/ijms232314971
Chicago/Turabian StyleRazman, Aimi Zafira, Yung-An Chua, Noor Alicezah Mohd Kasim, Alyaa Al-Khateeb, Siti Hamimah Sheikh Abdul Kadir, Siti Azma Jusoh, and Hapizah Nawawi on behalf of the MyHEBAT-FH Study Investigators. 2022. "Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing" International Journal of Molecular Sciences 23, no. 23: 14971. https://doi.org/10.3390/ijms232314971