S.N.A. KAMARUDDIN1, S.L. PEK1, S. DISSANAYAKE1, J.I. TANG1, J. HOE1, W.Y. WAN1, F. SIRAJ1, A. ZULKIFLI1, M.X. LIN1, Z.L. CHAN1, E.T.S LIM2
Khoo Teck Puat Hospital1, National Heart Centre Singapore2
Familial hypercholesteremia(FH) is an autosomal dominant genetic disease leading to elevated levels of plasma low-density lipoprotein cholesterol(LDL-c) and premature cardiovascular disease. The mutations commonly occur at the LDL Receptor(LDLR) or Apolipoprotein B(APOB) gene. Spectrum of mutations may differ among different cohorts. The aim of this study is to evaluate the types and locations of mutation in a local cohort of patients with FH.
Patients(probands) with possible or definite FH, based on Simon-Broome criteria, were recruited from June 2015-April 2021, from KTPH, AdMC, CGH, NUH, NHC, KKH, NTF, NHGP, SGH, SKH, and TTSH. Clinical data, family history, and blood or saliva samples were collected. DNA was extracted and Next-Generation Sequencing(NGS) was performed, using 26 lipid-related genes such as LDLR and APOB. Sanger Sequencing was used for validation while Multiplex Ligation-dependent Probe Amplification(MLPA) for LDLR, was used to detect any large mutations undetectable by NGS. Data analyses was done by Microsoft Excel.
Five hundred and eighty-nine patients were recruited and 207 pathogenic mutations were detected. 87.0% (n=180) were on LDLR and 8.2%(n=17) were on APOB. 4.8%(n=10) were detected by MLPA. The top three LDLR mutations are on exon 7, 9, and 12. Their respective values are 10%(n=18), 11.1%(n=20), and 15.6%(n=28). LDLR exon 12, p.(His583Tyr) is a hotspot mutation (n=22). For APOB mutations, exon 26 and 29 accounts for 88.2%(n=15) and 11.8%(n=2) respectively.
Using NGS, Sanger Sequencing, and MLPA, we identified monogenic mutations in our local population. Polygenic causes should be explored in future studies.