Genetic testing for familial hypercholesterolemia: Impact on diagnosis, treatment and cardiovascular risk

Abstract

Aims Familial hypercholesterolemia (FH) is the most common genetic disorder in medicine, with a prevalence of 1/250. Affected individuals have elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and, more recently, genetic testing. We sought to determine the impact of genetic testing on the: 1) diagnosis of ‘definite familial hypercholesterolemia’, 2) initiation and adherence of lipid-lowering therapy and 3) risk of ASCVD. Methods We performed a systematic review and meta-analysis, pooling odds ratios and 95% confidence intervals for ASCVD from studies comparing risk estimates in individuals harboring FH-causing variants and unaffected individuals. Results After screening 3304 unique publications, 56 studies were included in the analysis. 1) Genetic testing provided confirmation of FH in 28–80%, over clinical criteria alone, depending on the diagnostic algorithm and the method of analysis. In two large population-based studies comprising 76,751 individuals, an FH-causing variant was identified in only 1.7–2.5% of subjects with an LDL-C > 4.9 mmol/L (190 mg/dL). 2) A confirmed molecular diagnosis increased lipid-lowering therapy adherence (five studies, n = 4181 definite FH). 3) Loss-of-function variant of the LDLR were at a markedly increased risk of myocardial infarction (odds ratio 6.77, 95% confidence interval 4.75–9.66), and patients with a milder (hypomorphic) pathogenic LDLR change had a 4.4-fold increase in risk (odds ratio 4.4, 95% confidence interval 2.34–8.26), compared with controls. Conclusion DNA sequencing confirms the diagnosis of FH but has a poor yield in unselected patients whose sole criterion is an elevated LDL-C. Initiation and adherence to treatment is improved. The risk of ASCVD is 4.4- to 6.8-fold increased in patients with an FH-causing variant compared with controls, depending on the severity of the DNA change.

A Global Review on the Utility of Genetic Testing for Familial Hypercholesterolemia

“…Our findings are consistent with a recent systematic review and meta-analysis showing that FH genetic testing can confirm FH diagnosis over clinical criteria alone, depending on the diagnostic algorithm and the method of analysis [41]. However, given that eight of the 21 studies reviewed reported only two non-clinical outcomes (education on lifestyle management and genetic counseling) following FH genetic testing, with no particular consistency in reporting these outcomes, there is opportunity to determine broader, non-clinical outcomes following FH genetic testing (e.g., behavioral outcomes like statin treatment adherence).…”

Next-generation sequencing to confirm clinical familial hypercholesterolemia

“…Dutch Lipid Clinic Network (DLCN) criteria), ideally followed by DNA sequencing to identify variants in the LDLR, APOB and PCSK9 genes that cause FH. A genetic diagnosis of FH allows better CVD risk stratification, 2 increases therapy adherence of the diagnosed patient 3 and allows cascade testing of first-degree relatives. 4 Apart from the three canonical FH genes, pathogenic variants in other so-called 'minor FH' genes may also contribute to or mimic the FH phenotype.…”

“Apple does not fall far from the tree” – subclinical atherosclerosis in children with familial hypercholesterolemia

“…Recognition of genetic background of the FH becomes important nowadays because particular mutations were reported to affect phenotype of patients and due to new possibilities of treatment [ 33 – 37 ]. Unfortunately, no significant association between presence of presumed pathogenic gene variants and aggravation of atherosclerosis was observed.…”