Familial hypercholesterolaemia

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Inclusion criteria

Lipid levels either pre-treatment or highest on treatment:

  • Simon Broome criteria ‘definite familial hypercholesterolaemia’:
    • Abnormal lipids:
      • Total cholesterol >6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR
      • Total cholesterol >7.5 mmol/l (290 mg/dl), or LDL cholesterol above 4.9 mmol/l (190 mg/dl) in an adult


  1. Tendon xanthomas (TX) in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt)


  • Abnormal lipids:
    • Total cholesterol > 6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR
    • Total cholesterol >8.5 mmol/l, or LDL cholesterol above 5.5 mmol/l in an adult


  1. Family history of myocardial infarction below age of 50 in 2nd degree relative or below age 60 in 1st degree relative, OR
  2. Family history of raised cholesterol: >7.5 mmol/l in adult 1st or 2nd degree relative or > 6.7 mmol/l in child or sibling under 16


  • Polygenic risk 12-SNP gene score in the bottom two quartiles

Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.

In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Exclusion criteria:

  • Secondary causes of elevated LDL-C. Patients will only be eligible who have elevated LDL-C on measures taken on a fasting blood sample and after secondary causes of hyperlipidaemia have been excluded.
  • Recessive inheritance. Families showing a recessive pattern of inheritance will not be recruited.
  • Individuals with a fasting plasma Triglyceride level of over 2.5mmol/l will be excluded.

Prior genetic testing guidance

  •  Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition.
  • Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Prior genetic testing genes

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

  • LDLR, APOB and PCSK9
  • Polygenic risk 12-SNP gene score

Closing statement

These requirements will be kept under continual review during the main programme and may be subject to change.

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