Refinement of pathogenicity classification of variants associated with familial hypercholesterolemia: Implications for clinical diagnosis

J Clin Lipidol. 2021 Nov-Dec;15(6):822-831. doi: 10.1016/j.jacl.2021.10.001. Epub 2021 Oct 11.

Abstract

Background: The lack of functional evidence for most variants detected during the molecular screening of patients with clinical familial hypercholesterolemia (FH) makes the definitive diagnosis difficult.

Methods: A total of 552 variants in LDLR, APOB, PCSK9 and LDLRAP1 genes found in 449 mutation-positive FH (FH/M+) patients were considered. Pathogenicity update was performed following the American College of Medical Genetics and Genomics (ACMG) guidelines with additional specifications on copy number variants, functional studies, in silico prediction and co-segregation criteria for LDLR, APOB and PCSK9 genes. Pathogenicity of LDLRAP1 variants was updated by using ACMG criteria with no change to original scoring.

Results: After reclassification, the proportion of FH/M+ carriers of pathogenic (P) or likely pathogenic (LP) variants, and FH/M+ carriers of likely benign (LB) or benign (B) variants, was higher than that defined by standard criteria (81.5% vs. 79.7% and 7.1% vs. 2.7%). The refinement of pathogenicity classification also reduced the percentage of FH with variants of uncertain significance (VUS) (17.7% vs. 11.4%). After adjustment, the FH diagnosis by refined criteria best predicted LDL-C levels (Padj <0.001). Notably, FH with VUS variants had higher LDL-C than those with LB (all Padj ≤ 0.033), but similar to those with LP variants.

Conclusion: Accurate variant interpretation best predicts the increase of LDL-C levels and shows its clinical utility in the molecular diagnosis of FH.

Keywords: Genetic testing; Low density lipoprotein cholesterol; Molecular diagnosis; Monogenic familial hypercholesterolemia; Variants’ pathogenicity classification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Apolipoproteins B / genetics*
  • Child
  • Cholesterol, LDL / metabolism
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease / classification
  • Genetic Predisposition to Disease / genetics*
  • Heterozygote
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Hyperlipoproteinemia Type II / diagnosis
  • Hyperlipoproteinemia Type II / genetics*
  • Hyperlipoproteinemia Type II / metabolism
  • Male
  • Middle Aged
  • Mutation*
  • Proprotein Convertase 9 / genetics*
  • Receptors, LDL / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apolipoproteins B
  • Cholesterol, LDL
  • LDLRAP1 protein, human
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9