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Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B

Roeland Huijgen1, Iris Kindt, Sigrid W Fouchier

  • 1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Human Mutation
|May 28, 2010
PubMed

Insights

Familial hypercholesterolemia (FH) genetic screening sometimes identifies mutation carriers with normal LDL-C levels. This study proposes criteria to identify nonpathogenic sequence variants, aiding accurate FH diagnosis.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Molecular Biology

Background:

  • Familial hypercholesterolemia (FH) is characterized by elevated LDL-C, typically above the 90th percentile.
  • Genetic cascade screening reveals some LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C below the 75th percentile.
  • The nonpathogenicity of certain genetic sequence variants may explain these unexpectedly low LDL-C levels.

Purpose of the Study:

  • To establish criteria for assessing the pathogenicity of genetic mutations in FH.
  • To identify nonpathogenic sequence changes within LDLR and APOB genes.
  • To refine genetic screening programs for FH by distinguishing pathogenic from nonpathogenic variants.

Main Methods:

  • Proposed three criteria to assess mutation pathogenicity: LDL-C levels in carriers, comparison of carrier vs. non-carrier LDL-C, and medication usage.
  • Applied these criteria to mutations identified in over 50 untreated adult FH patients.
  • Utilized segregation analysis to confirm the nonpathogenicity of identified variants.

Main Results:

  • Forty-six mutations were analyzed in more than 50 untreated subjects.
  • Three mutations were classified as nonpathogenic based on the proposed criteria: one in LDLR (c.108C4A, exon 2) and two in APOB (c.13154T4C and c.13181T4C, exon 29).
  • Segregation analysis supported the nonpathogenic classification of these three sequence variants.

Conclusions:

  • The developed criteria effectively identify nonpathogenic sequence variants in FH genetic screening.
  • Accurate identification of nonpathogenic variants is crucial for precise FH diagnosis and management.
  • These criteria can improve the interpretation of genetic testing results in FH cascade screening programs.

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