Update of the Portuguese Familial Hypercholesterolaemia Study

Abstract

a b s t r a c tThe main aim of the Portuguese Familial Hypercholesterolaemia Study is to identify the genetic cause of hypercholesterolaemia in individuals with a clinical diagnosis of Familial Hypercholesterolaemia (FH). A total of 1340 blood samples were collected from 482 index patients and 858 relatives with the collaboration of clinicians from several hospitals all over the country. The genetic diagnosis of FH in this study is based on the analyses of three genes: LDLR, APOB and PCSK9. In the last 10 years, the Portuguese FH Study identified a genetic defect in a total of 171 index patients, corresponding to an overall of 48% of the total received cases with clinical diagnosis of FH. Although the Simon Broome FH register criteria have been adapted to our study, 59 patients that did not fulfil all criteria were included in the study and a mutation causing disease was identified in 8 of these patients. In the LDLR gene were found 80 different mutations in 165 unrelated index patients: 159 heterozygous, 3 compounds heterozygous and 3 true homozygous. The APOB p.Arg3527Gln and the PCSK9 p.Asp374His mutation were not found in any of our patients since our last report, but a novel mutation in the APOB gene, predicted to cause a single amino acid substitution p.Tyr3560Cys, was found in one patient. The cascade screening in relatives of these 171 index patients allowed the identification and genetic characterization of a total of 404 FH patients in Portugal.

Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia

“…The genetic diagnosis of FH was performed by the molecular analysis of APOB (two fragments of exons 26 and 29), LDLR (including the study of splice regions and large rearrangements), and PCSK9 genes as reported previously ( 26 ). Mutations were considered to be pathogenic if cosegregation of the mutation with the phenotype was observed and if mutations were previously described in other populations.…”

“…No mutations were found in the PCSK9 gene. In the remaining 148 children (62.4%), no mutations considered pathogenic were identifi ed using the current molecular biology techniques previously published ( 26,27 ).…”

“…A total of 237 unrelated children (2-17 years old) were referred as index patients to the Portuguese FH Study (PFHS) (24)(25)(26)(27) during 1999-2012, mainly by pediatricians, cardiologists, and clinical geneticists countrywide. Only children with two independent altered fasting lipid profi les were recruited for this study.…”

Familial Hypercholesterolemia in an Azorean Family: A Novel Mutation in the Low-Density Lipoprotein Receptor Gene

“…In the last ten years, the Portuguese FH Study identified 80 different mutations in the LDLR gene, in 165 unrelated index patients, 34 being exclusive to the Portuguese population [22]. The mutation found in the LDLR gene of our family has not been previously described in the literature, and is to date exclusive to our study population, so we call it Azorean-1 mutation.…”

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

“…28 In addition, a Portuguese ADH study found only 48% of its total received cases with clinical diagnosis of ADH had genetic defects on LDLR, APOB or PCSK9, leaving the other 52% of ADH cases with possible undiscovered gene mutations. 29 In a study by Garcia et al, 30 the researchers used gene chip (robo arrays) to resequence the coding regions of 10 key genes of lipid metabolism in 80 dyslipidemic cases. In all, 14 non-synonymous and 22 synonymous SNPs were identified, which were confirmed by conventional sequencing.…”