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New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

Sandy Elbitar1,2,3, Delia Susan-Resiga4, Youmna Ghaleb1,2,3

  • 1INSERM LVTS U1148, hôpital Bichat-Claude Bernard, Paris, France.

Scientific Reports
|February 2, 2018
PubMed

Insights

Researchers identified new mutations in the APOB gene and the first compound heterozygote for APOB and PCSK9 mutations in families with autosomal dominant hypercholesterolemia (ADH). This advances ADH diagnosis and treatment.

Area of Science:

  • Genetics
  • Cardiovascular Disease
  • Molecular Biology

Background:

  • Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by elevated LDL-C levels, significantly increasing the risk of coronary heart disease.
  • Four genes (LDLR, APOB, PCSK9, APOE) are currently known to be implicated in ADH.

Purpose of the Study:

  • To identify novel mutations in known ADH-associated genes or discover new genes involved in the condition.
  • To investigate the genetic basis of ADH in thirteen French families.

Main Methods:

  • Exome sequencing was performed on probands after excluding mutations in LDLR, PCSK9, APOE, and specific APOB exons.
  • Segregation analysis and in-silico methods were used to assess the pathogenicity of identified mutations.
  • Functional studies were conducted to elucidate the impact of a specific PCSK9 mutation.

Main Results:

  • A novel p.Arg50Gln mutation in the APOB gene was identified in one family, located in a previously unassociated region.
  • A patient with a severe ADH phenotype presented with both an APOB mutation (p.Ala3396Thr) and a PCSK9 mutation (p.Arg96Cys), representing the first reported compound heterozygote.
  • Functional studies confirmed that the p.Arg96Cys PCSK9 mutation increases LDL receptor degradation.

Conclusions:

  • Next-Generation Sequencing (NGS) is a powerful approach for identifying new mutations and compound heterozygotes in ADH.
  • These findings contribute to a better understanding of ADH genetics, potentially improving diagnostic and therapeutic strategies.

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