S.PEK1, S. DISSANAYAKE1, JIS TANG1, JKM HOE2, WY WAN1, F SIRAJ1, ZULKIFLI A1, MXQ LIN1, EZL CHAN1, KAMARUDDIN SNA1, ETS LIM3, CHUA TSJ3, TAN JL3, LAM CSP3, F YAP4, LOH WJ5, TAI ES6, DRUM CL6, RACELL AS7, JONNA LBE7, DALAN R8, ABU BAKAR SZ8, YANG L8, KOH NSY3, TIONG YS9, TAN HC10, CHEN QF10, S. TAVINTHARAN2
Khoo Teck Puat Hospital1, Admiralty Medical Centre2, National Heart Centre Singapore3, KK Women’s & Children’s Hospital4, Changi General Hospital5, National University Hospital6, National University of Singapore7, Tan Tock Seng Hospital8, Ng Teng Fong General Hospital9, Singapore General Hospital10
Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease characterized by very high plasma low density lipoproteins cholesterol (LDL-C), increasing the risk for premature cardiovascular disease (CVD) by 20-fold, compared to general population. Prevalence of FH is estimated to be 1 in 250 in the population but only 10% of them are diagnosed. Cascade testing is the most cost-effective method of identifying more individuals with FH. We aim to evaluate the diagnostic yield of cascade screening in patients with genetically confirmed FH.
Probands were recruited based on Simon Broome Criteria from Endocrine and Cardiology clinics at Yishun Health, TTSH, NHGP, NHCS, SGH, CGH, SKH, NUHS and NTFGH. Next generation sequencing was used to detect pathogenic/likely pathogenic mutations in LDLR, APOB, PCSK9, LDLRAP1 and 22 other lipid-related genes. In those with mutations, cascade screening was performed. Lipid and gene profiles, by capillary sequencing, were tested in family members (FM). Statistical analysis was performed using STATA.
Out of 610 probands, there were 175 and 17 LDLR and APOB mutations, respectively. One hundred and ninety-three FM were screened through 192 probands, with 100 of them being mutation-positive (M+). Highest documented total cholesterol(TC) and LDL-C of probands versus M+:[7.9(7.0 – 9.5) vs 6.6(5.8-7.7),p<0.0001]mmol/l and [6.2(5.4-7.6) vs 4.9 (4.1-5.9),p<0.0001]mmol/l. Of the FM who were M+, 59 (59%) were previously undiagnosed and in those previously diagnosed, their LDL-C was (5.1±0.3)mmol/l on recruitment.
The local cascade screening in FH yielded 0.5new case per proband. FM (M+) had lower TC and LDL-C than probands and were mostly under-treated.