Description
Familial Hypercholesterolaemia eligibility statement:

Familial Hypercholesterolaemia inclusion criteria (33440)
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
    AND
    -Tendon xanthomas (TX) in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt) 
OR
    •	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
    AND
    - Family history of myocardial infarction below age of 50 in 2nd degree relative or below   age 60 in 1st degree relative, OR
    - 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
AND
    •	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.

Familial Hypercholesterolaemia exclusion criteria (33440)
•	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 (33440)
- 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.

Familial Hypercholesterolaemia prior genetic testing genes (33440)
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 (33440)
These requirements will be kept under continual review during the main programme and may be subject to change.

6 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Ellen Thomas (Genomics England)

    Group: other
    Workplace: other

  • steve Humphries (UCL)

    Group: GeCIP domain
    Workplace: Research lab

  • Ellen Thomas (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Helen Brittain (Genomics England Curator)

    Group: Other
    Workplace: Other

43 Entities

43 reviewed, 8 green

List Entity Reviews Mode of inheritance Details
43 Entitiess
Green Green List (high evidence)
ABCG5
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
Phenotypes
  • Hypercholesterolemia
Tags
Green Green List (high evidence)
ABCG8
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Gene part of the 6-SNP LDL-C gene score calculation (Futema et al, 2015)
  • Hypercholesterolemia
Tags
Green Green List (high evidence)
APOB
4 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Gene part of the 6-SNP LDL-C gene score calculation (Futema et al, 2015)
  • Ag linked Hypobetalipoproteinemia
  • Hypobetalipoproteinemia, normotriglyceridemic
  • Hypercholesterolemia, due to ligand-defective apo B, 144010
  • Familial Hypercholesterolemia
  • Hypercholesterolemia
  • Familial Hypercholesterolaemia
Tags
Green Green List (high evidence)
APOE
3 reviews
1 green 1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Autosomal dominant hypercholesterolaemia
Tags
Green Green List (high evidence)
LDLR
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Gene part of the 6-SNP LDL-C gene score calculation (Futema et al, 2015)
  • C3 Hypercholesterolemia, familial, 143890
  • LDL cholesterol level QTL2, 143890
  • Familial Hypercholesterolemia
  • Hypercholesterolemia
  • Familial Hypercholesterolaemia
Tags
Green Green List (high evidence)
LDLRAP1
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Hypercholesterolemia, familial, autosomal recessive, 603813
  • Familial Hypercholesterolemia
  • Hypercholesterolemia
  • Familial Hypercholesterolaemia
Tags
Green Green List (high evidence)
LIPA
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
Phenotypes
  • Hypercholesterolemia
  • Lysosomal acid lipase deficiency
Tags
Green Green List (high evidence)
PCSK9
4 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Hypercholesterolemia, familial, 3, 603776
  • {Low density lipoprotein cholesterol level QTL 1}, 603776
  • Familial Hypercholesterolemia
  • Hypercholesterolemia
  • Familial Hypercholesterolaemia
Tags
Red Red List (low evidence)
ABCA1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Tangier disease, 205400
  • HDL deficiency, type 2, 604091
  • {Coronary artery disease in familial hypercholesterolemia, protection against}, 143890
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
ACE
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • {Myocardial infarction, susceptibility to}
  • {Alzheimer disease, susceptibility to}, 104300
  • {Microvascular complications of diabetes 3}, 612624
  • [Angiotensin I-converting enzyme, benign serum increase]
  • {SARS, progression of}
  • Renal tubular
Tags
Red Red List (low evidence)
ANGPTL3
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
APOA1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
APOA2
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Apolipoprotein A-II deficiency {Hypercholesterolemia, familial, modification of}, 143890
Tags
Red Red List (low evidence)
APOA5
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hyperchylomicronemia, late-onset 144650
  • {Hypertriglyceridemia, susceptibility to} 145750
Tags
Red Red List (low evidence)
APOC2
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
Phenotypes
  • Hyperlipoproteinemia, type Ib 207750
Tags
Red Red List (low evidence)
APOC3
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
CELSR2
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Gene part of the 6-SNP LDL-C gene score calculation (Futema et al, 2015)
Tags
Red Red List (low evidence)
CETP
2 reviews
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
CYP27A1
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebrotendinous xanthomatosis, 213700
  • Cerebrotendinous Xanthomatosis
  • CEREBROTENDINOUS XANTHOMATOSIS
Tags
Red Red List (low evidence)
EPHX2
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypercholesterolemia, familial, due to LDLR defect, modifier of, 143890
Tags
Red Red List (low evidence)
ESR1
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Estrogen resistance, 615363
  • {HDL response to hormone replacement, augmented}
  • {Migraine, susceptibility to}, 157300
  • {Atherosclerosis, susceptibility to}
  • {Myocardial infarction, susceptibility to}, 608446
  • {Breast cancer}, 114480 (1)
  • {HDL response to hormone replacement, augmented}
  • {Migraine, susceptibility to}, 157300
  • {Atherosclerosis, susceptibility to}
  • {Myocardial infarction, susceptibility to}, 608446
  • {Breast cancer}, 114480 (1)
Tags
Red Red List (low evidence)
F13A1
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Factor XIIIA deficiency, 613225
  • {Myocardial infarction, protection against}, 608446
  • {Venous thrombosis, protection against}, 188050
  • {Myocardial infarction, protection against}, 608446
  • {Venous thrombosis, protection against}, 188050
Tags
Red Red List (low evidence)
F7
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Factor VII deficiency, 227500
  • {Myocardial infarction, decreased susceptibility to}, 608446
Tags
Red Red List (low evidence)
GCLC
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency, 230450
  • {Myocardial infarction, susceptibility to}, 608446
  • Myocardial infarction, susceptibility to, 608446
Tags
Red Red List (low evidence)
GCLM
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Myocardial infarction, susceptibility to, 608446
Tags
Red Red List (low evidence)
GHR
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Laron dwarfism, 262500
  • Short stature, 604271
  • {Hypercholesterolemia, familial, modification of}, 143890
  • Increased responsiveness to growth hormone
Tags
Red Red List (low evidence)
GPD1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
GPIHBP1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
HFE
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
Tags
Red Red List (low evidence)
ITGB3
1 review
1 red
Not set
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • PL(A) platelet antigen Glanzmann thrombasthenia, 273800
  • Thrombocytopenia, neonatal alloimmune
  • {Myocardial infarction, susceptibility to}, 608446
  • Purpura, posttransfusion
  • Bleeding disorder, platelet-type, 16, autosomal dominant, 187800
Tags
Red Red List (low evidence)
LCAT
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
LIPC
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
LMF1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
LPL
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
MTTP
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
MYLIP
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
Tags
Red Red List (low evidence)
NYNRIN
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
Tags
Red Red List (low evidence)
SAR1B
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
SCARB1
1 review
1 red
Not set
Sources
  • Emory Genetics Laboratory
Phenotypes
  • Hypercholesterolemia
Tags
Red Red List (low evidence)
SLC22A1
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
Tags
Red Red List (low evidence)
SREBF2
1 review
Unknown
Sources
  • Literature
Phenotypes
  • Familial Hypercholesterolaemia
Tags
Red Red List (low evidence)
ST3GAL4
1 review
1 red
Not set
Sources
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
Tags
Red Red List (low evidence)
STAP1
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • hypercholesterolemia
Tags

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