Elsevier

The American Journal of Cardiology

Volume 102, Issue 9, 1 November 2008, Pages 1187-1193.e1
The American Journal of Cardiology

Preventive cardiology
Comparison of Genetic Versus Clinical Diagnosis in Familial Hypercholesterolemia

https://doi.org/10.1016/j.amjcard.2008.06.056Get rights and content

Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic testing for low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB) gene defects is the preferable diagnostic method, but the best phenotype indication to proceed with genetic diagnosis has not been established. The aim of this study was to assess the predictive and accuracy values of standard diagnostic criteria for detecting disease-causing mutations in 825 subjects with clinical FH aged ≥14 years from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations were detected in 459 subjects (55.6%). By logistic regression analysis, familial or personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated with genetic diagnosis (p <0.005, R2 = 0.41). In subjects without familial or personal histories of TX, the diagnostic criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project, based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity of 71.1%, and accuracy of 71.6%. LDL cholesterol ≥190 mg/dl in subjects with familial or personal histories of TX and ≥220, ≥225, and ≥235 mg/dl in those without such histories aged <30, 30 to 39, and ≥40 years, respectively, showed sensitivity of 91.1%, specificity of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of diagnostic criteria for FH was validated in an independent group of 440 subjects from 6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol cut-off values have the highest value for clinical diagnosis and indication of genetic testing in FH.

Section snippets

Methods

From May 2004 to November 2007, all consecutive subjects aged ≥14 years who were evaluated at 3 large lipid clinics located in university hospitals in Spain and underwent the FH genetic diagnostic procedure using Lipochip were included in the study. Subjects underwent genetic studies when the attending physician suspected FH because of familial very high total cholesterol or LDL cholesterol levels, with or without familial or personal histories of premature CAD and with or without tendon

Results

Table 1 lists the clinical characteristics and lipid profiles of the study population. There were 366 subjects (44.4%) with clinical suspicion of FH in whom the results for mutations were negative and 459 subjects (55.6%) with functional mutations in the LDLR or APOB genes. FH mutation carriers (LDLR/APOB+) were younger than those without genetic defects (LDLR/APOB−). Women predominated in the LDLR/APOB+ group. Classic clinical features of FH, such as family history of premature coronary or

Discussion

In this work, we performed phenotype-genotype comparisons in 825 subjects with clinical suspicion of FH, of whom 56% had the diagnosis genetically confirmed. We found that histories of TX in patients or their relatives was highly predictive of the presence of molecular defects in the LDLR or APOB gene in those aged >14 years with LDL cholesterol levels ≥190 mg/dl. We also defined age-specific LDL cholesterol thresholds with good predictive power for a genetic diagnosis in subjects without

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    This study was supported by grants PI05/0247, PI06/0365, PI06/1402 (Fondo de Investigaciones Sanitarias de la Seguridad Social) and RTIC C06/01 (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares) from the Spanish Ministry of Health, Madrid, Spain, and grant SAF2005-07042 from the Spanish Ministry of Education and Science, Madrid, Spain.

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