Expanding the genetic spectrum for Chinese familial hypercholesterolemia population with six genetic mutations...

This study was to reveal the prevalence of definite familial hypercholesterolemia (FH) in the hospital-visiting population, determine the pathogenic mutation detection rate in clinically diagnosed definite FH patients, and expand the FH mutation spectrum in China.

Blood lipid profiles of 41,803 patients visiting the hospital were investigated and 4967 patients with clinical diagnoses of other metabolic diseases were excluded. One hundred and seventy-three (0.41%) received a definite diagnosis of FH according to the Dutch Lipid Clinical Network Criteria-Chinese Revised Version (DLCN-CRV), and 18 patients subsequently agreed to undergo genetic testing. A next-generation sequencing (NGS)-based laboratory-developed test covering the exonic regions of 24 lipid metabolism-related genes was conducted alongside in silico analyses to identify possible FH mutations in 16 definite FH patients, according to the American College of Medical Genetics and Genomics (ACMG) criteria. Sanger sequencing was used to confirm mutations, and SWISS-MODEL was used to simulate the molecular structures of the confirmed protein-carrying mutations.

The FH prevalence was 0.41% for the 41,803 individuals (DLCN-CRV grade >8) and 25% of definite FH patients carried six FH pathogenic mutations (≥ACMG Class 4). All genetic variants were confirmed by Sanger sequencing. Five pathogenic variants on the LDLR gene (NM_000527: c.C1783T: p.R595W, c.T493G: p.W165G, c.G1879A: p.A627T, c.G682T: p.E228X, and exon10: c.G1432A: p.G478R) and one pathogenic variant on APOB (NM_000384: c.C10579T: p.R3527W) in 25% of the identified definite FH patients. Two pathogenic mutations, c.T493G (p.W165G) and c.C1783T (p.R595W), were added to the current genetic spectrum of FH in China.

This study contributes to improving the current FH detection rate and genetic screening strategies; it provides new directions for treatment, management, and drug development.