Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease

BackgroundPatients with monogenic familial hypercholesterolemia (FH) have high risk for coronary artery disease (CAD). A recent FH Expert Panel suggested that FH was underdiagnosed and undertreated which needs early diagnosis. Moreover, the proportion of DNA-confirmed FH patients hospitalized with very early-onset (35years) CAD remains uncertain.MethodsOne hundred and five patients with age35years and LDL-C3.4mmol/L were tested for 9 genes (LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8). Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria for FH were also performed.ResultsThe prevalence of genetically confirmed FH was 38.1% (n=40) in 105 patients. DLCN categorized 26.7% patients to probable and definite FH while SB identified 17.1% of patients with possible to definite FH. Twenty-five (62.5%) and seventeen (42.5%) patients with pathogenic mutations were undiagnosed according to SB and DLCN criteria. FH variant carriers, especially homozygotes, had significantly higher plasma LDL-C levels. The best LDL-C threshold for genetically confirmed FH was 4.56mmol/L in the present study.ConclusionsFH is really a common cause for very young CAD patients (35years) with a 38.1% of causative mutations in China and best LDL-C threshold for predicting mutations was 4.56mmol/L. The underdiagnostic rate of clinical criteria was around 42.5-62.5%, suggesting that the expanded genetic testing could indeed promote the diagnosis of FH.