Mutational analysis of the LDLR gene in a cohort of Colombian families with familial hypercholesterolemia


      • p.W4X, p.D139G, and p.G396D mutations were identified in five Colombian families.
      • p.G396D mutation may be frequent in the Colombian population.
      • c.1187-1G > T variant accompanied the p.G396D mutation in three affected families.
      • 79% of the study population did not have mutation in the LDLR gene.


      Background and aims

      Familial hypercholesterolemia (FH) is characterized by elevated serum cholesterol levels due to high low-density lipoprotein (LDL) cholesterol levels. FH is an autosomal dominant genetic disorder and one of the most common dominant hereditary diseases in the world. However, the frequency of mutations in Colombia is unknown. The purpose of this preliminary study was to identify mutations in the LDL receptor (LDLR) gene in a Colombian population with FH.


      The study included 24 families with clinical diagnosis of sure/probable FH. The 18 exons of the LDLR were sequenced by Sanger method.


      Among 18 variants identified, 3 were known pathogenic mutations and were identified in nine individuals in five unrelated families. Five affected individuals were heterozygous for one mutation each. They were the p.W4X in two, the p.D139G in two and the p.G396D in one. Two affected individuals were homozygous for p.G396D. The variant c.1187-1G > T, which has uncertain significance in FH pathogenesis, was present in all the individuals with the p.D139G mutation.


      In total, 18 variants were identified, of which 14 correspond to known nonpathogenic variants. Three pathogenic variants were identified in the LDLR. No pathological mutations were identified in the LDLR in 79% of the study population.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Marais A.D.
        Familial hypercholesterolaemia.
        Clin. Biochem. Rev. 2004; 25 (PMC1853359): 49-68
        • Stoll M.
        • Lorenzo M.
        • Raggio V.
        • Esperón P.
        • Zelarayan M.
        Previniendo el infarto en el adulto joven: GENYCO, un registro nacional de hipercolesterolemia familiar.
        Rev. Urug. Cardiol. 2011; 26 (Available from) (ISSN 0797-0048): 16-26
        • Thorogood M.
        • Broom G.S.
        Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
        BMJ. 1991; 303 (PMC1671226): 893-896
        • Slack J.
        Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states.
        Lancet. 1969; 2: 1380-1382
        • Futema M.
        • Whittall R.A.
        • Kiley A.
        • Steel L.K.
        • Cooper J.A.
        • Badmus E.
        • Leigh S.E.
        • Karpe F.
        • Neil H.A.
        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
        • Mansur F.
        • España H.
        • Dueñas C.
        Variables asociadas a mortalidad por infarto del miocardio en adultos mayores de 75 años en Cartagena de Indias, Colombia: un estudio piloto.
        Rev. Colomb. Cardiol. 2011; 18 (Available from: <>. ISSN 0120-5633): 192-198
        • Di Taranto M.D.
        • D'Agostino M.N.
        • Fortunato G.
        Functional characterization of mutant genes associated with autosomal dominant familial hypercholesterolemia: integration and evolution of genetic diagnosis.
        Nutr. Metabol. Cardiovasc. Dis. 2015; 25: 979-987
        • Fellin R.
        • Arca M.
        • Zuliani G.
        • Calandra S.
        • Bertolini S.
        The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification.
        Gene. 2015; 555: 23-32
        • Fernandez-Higuero J.A.
        • Etxebarria A.
        • Benito-Vicente A.
        • Alves A.C.
        • Arrondo J.L.
        • Ostolaza H.
        • Bourbon M.
        • Martin C.
        Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity.
        Sci. Rep. 2015; 5: 18184
        • Gu H.M.
        • Zhang D.W.
        Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9.
        J Biomed Res. 2015; 29: 356-361
        • Sjouke B.
        • Hovingh G.K.
        • Kastelein J.J.
        • Stefanutti C.
        Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.
        Curr. Opin. Lipidol. 2015; 26: 200-209
        • Stenson P.D.
        • Mort M.
        • Ball E.V.
        • Evans K.
        • Hayden M.
        • Heywood S.
        • Hussain M.
        • Phillips A.D.
        • Cooper D.N.
        The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.
        Hum. Genet. 2017; 136: 665-677
        • Marks D.
        • Thorogood M.
        • Neil H.A.
        • Humphries S.E.
        A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
        Atherosclerosis. 2003; 168: 1-14
        • Civeira F.
        • Ros E.
        • Jarauta E.
        • Plana N.
        • Zambon D.
        • Puzo J.
        • Martinez de Esteban J.P.
        • Ferrando J.
        • Zabala S.
        • Almagro F.
        • et al.
        Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.
        Am. J. Cardiol. 2008; 102 (1193 e1181): 1187-1193
        • Mata N.
        • Alonso R.
        • Badimon L.
        • Padro T.
        • Fuentes F.
        • Muniz O.
        • Perez-Jimenez F.
        • Lopez-Miranda J.
        • Diaz J.L.
        • Vidal J.I.
        • et al.
        Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish familial hypercholesterolemia longitudinal cohort study (SAFEHEART).
        Lipids Health Dis. 2011; 10: 94
        • 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
        • Marduel M.
        • Carrie A.
        • Sassolas A.
        • Devillers M.
        • Carreau V.
        • Di Filippo M.
        • Erlich D.
        • Abifadel M.
        • Marques-Pinheiro A.
        • Munnich A.
        • et al.
        Molecular spectrum of autosomal dominant hypercholesterolemia in France.
        Hum. Mutat. 2010; 31: E1811-E1824
        • Chmara M.
        • Wasag B.
        • Zuk M.
        • Kubalska J.
        • Wegrzyn A.
        • Bednarska-Makaruk M.
        • Pronicka E.
        • Wehr H.
        • Defesche J.C.
        • Rynkiewicz A.
        • et al.
        Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.
        J. Appl. Genet. 2010; 51: 95-106
        • Bernal J.
        • Suárez F.
        La carga de la enfermedad genética en Colombia, 1996-2025.
        Universitas Médica. 2007; 49 (Available from:<> ISSN 0041-9095): 12-28
        • Nadelmann J.
        • Frishman W.H.
        • Ooi W.L.
        • Tepper D.
        • Greenberg S.
        • Guzik H.
        • Lazar E.J.
        • Heiman M.
        • Aronson M.
        Prevalence, incidence and prognosis of recognized and unrecognized myocardial infarction in persons aged 75 years or older: the Bronx Aging Study.
        Am. J. Cardiol. 1990; 66: 533-537
        • Leal M.F.
        • Souza Filho N.F.
        • Haggi Filho H.
        • Klosoviski E.R.
        • Munhoz E.C.
        Acute myocardial infarction in elderly patients: comparative analysis of the predictors of mortality. The elderly versus the young.
        Arq. Bras. Cardiol. 2002; 79: 363-374
        • Varret M.
        • Abifadel M.
        • Rabes J.P.
        • Boileau C.
        Genetic heterogeneity of autosomal dominant hypercholesterolemia.
        Clin. Genet. 2008; 73: 1-13
        • Paththinige C.S.
        • Sirisena N.D.
        • Dissanayake V.
        Genetic determinants of inherited susceptibility to hypercholesterolemia - a comprehensive literature review.
        Lipids Health Dis. 2017; 16: 103
        • Futema M.
        • Shah S.
        • Cooper J.A.
        • Li K.
        • Whittall R.A.
        • 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
        • Wiegman A.
        • Gidding S.S.
        • Watts G.F.
        • Chapman M.J.
        • Ginsberg H.N.
        • Cuchel M.
        • Ose L.
        • Averna M.
        • Boileau C.
        • Boren J.
        • et al.
        Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
        Eur. Heart J. 2015; 36: 2425-2437