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Updated: Feb 20, 2026

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Familial hypercholesterolemia concealed by a protein-truncating variant of PCSK9

Hayato Tada1, Atsushi Furukawa1, Masayuki Takamura1

  • 1Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

Journal of Clinical Lipidology
|February 18, 2026
PubMed

Insights

Familial hypercholesterolemia (FH) is a common genetic condition. A rare family with FH showed mitigated symptoms due to a natural PCSK9 variant, suggesting long-term PCSK9 inhibition may be safe for FH patients.

Area of Science:

  • Genetics and Cardiovascular Medicine
  • Lipid Metabolism and Atherosclerosis

Background:

  • Familial hypercholesterolemia (FH) is a prevalent inherited dyslipidemia and a significant risk factor for early coronary artery disease.
  • Statins are the first-line treatment for FH, but often fail to normalize low-density lipoprotein cholesterol (LDL-C) levels.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are used as add-on therapy, but their long-term safety profile remains uncertain.

Purpose of the Study:

  • To investigate a rare family with FH exhibiting mitigated phenotypes.
  • To explore the potential impact of a co-existing genetic condition on FH severity.
  • To assess the implications for long-term PCSK9 inhibition therapy in FH.

Main Methods:

  • Case report of an extremely rare family.
  • Genetic analysis to identify causative variants.
  • Phenotypic evaluation of lipid profiles and cardiovascular risk.

Main Results:

  • The family presented with FH phenotypes that were unexpectedly mitigated.
  • A co-existing familial hypobetalipoproteinemia was identified, caused by a protein-truncating PCSK9 variant.
  • This genetic interaction led to reduced LDL-C levels and milder FH presentation.

Conclusions:

  • A naturally occurring PCSK9 variant can mitigate FH phenotypes.
  • This case provides evidence suggesting potential long-term safety and efficacy of PCSK9 inhibition in FH patients.
  • Further research into genetic interactions influencing lipid disorders is warranted.

Keywords:
Familial hypercholesterolemiaFamilial hypobetalipoproteinemiaGeneticsLDL cholesterolPCSK9

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