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BMC Med Genet ; 16: 86, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26415676

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is one of the commonest monogenic disorders, predominantly inherited as an autosomal dominant trait. When untreated, it results in early coronary heart disease. The vast majority of FH remains undiagnosed in Latvia. The identification and early treatment of affected individuals remain a challenge worldwide. Most cases of FH are caused by mutations in one of four genes, APOB, LDLR, PCSK9, or LDLRAP1. The spectrum of disease-causing variants is very diverse and the variation detection panels usually used in its diagnosis cover only a minority of the disease-causing gene variants. However, DNA-based tests may provide an FH diagnosis for FH patients with no physical symptoms and with no known family history of the disease. Here, we evaluate the use of targeted next-generation sequencing (NGS) to identify cases of FH in a cohort of patients with coronary artery disease (CAD) and individuals with abnormal low-density lipoprotein-cholesterol (LDL-C) levels. METHODS: We used targeted amplification of the coding regions of LDLR, APOB, PCSK9, and LDLRAP1, followed by NGS, in 42 CAD patients (LDL-C, 4.1-7.2 mmol/L) and 50 individuals from a population-based cohort (LDL-C, 5.1-9.7 mmol/L). RESULTS: In total, 22 synonymous and 31 nonsynonymous variants, eight variants in close proximity (10 bp) to intron-exon boundaries, and 50 other variants were found. We identified four pathogenic mutations (p.(Arg3527Gln) in APOB, and p.(Gly20Arg), p.(Arg350*), and c.1706-10G > A in LDLR) in seven patients (7.6 %). Three possible pathogenic variants were also found in four patients. CONCLUSION: NGS-based methods can be used to detect FH in high-risk individuals when they do not meet the defined clinical criteria.


Assuntos
LDL-Colesterol/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hiperlipoproteinemia Tipo II/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína B-100/genética , Estudos de Coortes , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Feminino , Genética Populacional , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Letônia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Adulto Jovem
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