New prediction model identifies more young individuals with FH for DNA screening

Selection of individuals for genetic testing for familial hypercholesterolaemia: development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia

Literature - Besseling J et al., Eur Heart J Lipids 2016

Besseling J, Reitsma JB, Gaudet D, et al.
Eur Heart J Lipids 2016;published online ahead of print


FH is a monogenic disorder of lipid metabolism, seen as either the rare homozygous, or the more common heterozygous form (HeFH) [1]. Patients with HeFH have markedly elevated LDL-C levels and without treatment, they are exposed to a 3-4-fold increase of CV risk compared with the general population [2,3]. Hence, early detection of HeFH is very important and the definite diagnosis is possible by identifying a molecular defect in one of three different genes [4]: the LDL receptor (LDLR), the apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9).
Although the identification of HeFH patients with genetic cascade screening and their treatment with statins is recommended in guidelines and was shown to be cost-effective, the selection of patients for genetic testing in clinical practice remains challenging [5,6]. The available algorithms [7-9] fail to identify young individuals, leading to under-diagnosis and under-treatment of young HeFH patients because [10,11]: 
  • the presence of tendon xanthomas is an important criterion, but it is a rare finding in young individuals
  • fixed, non-age-adjusted cut-off values for LDL-C are used to classify patients
  • the required information on family history of lipid disorders and premature CV is often absent
In this study, a prediction model was developed and externally validated, with the objective to predict the presence of an FH causing mutation, thereby enabling the physician to select eligible patients for DNA analysis for FH mutations. The development cohort consisted of all 26,167 FH patients and 37,939 unaffected relatives who participated in the Dutch FH screening programme from 1994 to 2014, and the validation cohort consisted of consecutive patients, suspected for FH, attending the outpatient lipid clinic in Saguenay (Quebec) from 1993 to 2014.

Main results

Prediction model:
The final prediction model included age, sex, levels of LDL-C, HDL-C, and triglycerides, history and age of CVD, use of statins, smoking, alcohol, and presence of hypertension. The regression coefficients of the predictors were used to construct an interactive web-based calculator that can be used to calculate the probability of the presence of an FH mutation in individual subjects

Model performance in the development cohort:
The AUC of the final model was 85.4% (95% CI: 85.0–85.9), and the slope of the calibration line was 1.02 (optimal slope is 1.00).

Prediction example: out of 29,331 (45.8%) persons who had a predicted probability of 0.30 or lower:
  • 25,473 (86.8%) did not carry an FH mutation
  • 3,857 were found to have an FH mutation (14.7% of all FH patients)

External validation
The AUC of the final model was 95.4% (95% CI: 94.7–96.1) in the external validation cohort, and the slope of the calibration line was 1.06.


A new prediction model developed to identify the presence of a deleterious FH mutation showed good discrimination and calibration. This model might add value for the selection of individuals eligible for DNA analysis for an FH mutation, particularly at young age.

Find this article online at Eur Heart J Lipids


1. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J 2014;36:560–565.
2. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. p. 2863–2913. Chapter 120.
3. Huijgen R, Kindt I, Defesche JC, et al. Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. Eur Heart J 2012;33:2325–2330.
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8. Williams RR, Hunt SC, Schumacher MCC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993;72:171–176.
9. Familial Hypercholesterolemia–report of a second WHO consultation. Geneva: WHO; 1998.
10. Damgaard D, Larsen ML, Nissen PH, et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis 2005;180:155–160.
11. Futema M, Whittall RA, Kiley A, et al. 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.

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