Highlights
- •Scoring criteria have been developed to select patients for DNA testing for FH.
- •623 patients presenting to lipid clinics across Wales had DNA testing.
- •85% scoring 15 had a mutation compared to 4% in those scoring 5 or less.
- •These criteria are a useful tool for the diagnosis of Familial Hypercholesterolaemia.
Abstract
Background/Objective
Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density
Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the
demonstration of a pathogenic mutation. The Wales FH service has developed scoring
criteria to guide selection of patients for DNA testing, for those referred to clinics
with hypercholesterolaemia. The criteria are based on a modification of the Dutch
Lipid Clinic scoring criteria and utilise a combination of lipid values, physical
signs, personal and family history of premature cardiovascular disease. They are intended
to provide clinical guidance and enable resources to be targeted in a cost effective
manner.
Methods
623 patients who presented to lipid clinics across Wales had DNA testing following
application of these criteria.
Results
The proportion of patients with a pathogenic mutation ranged from 4% in those scoring
5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest
discriminatory factor. Scores gained from physical signs, family history, coronary
heart disease, and triglycerides also showed a gradient in mutation pick-up rate according
to the score.
Conclusion
These criteria provide a useful tool to guide selection of patients for DNA testing
when applied by health professionals who have clinical experience of FH.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Familial hypercholesterolaemia.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic Basis of Inherited Disease. McGraw Hill, New York1995: 1981-2030
- Higher prevalence of familial hypercholesterolemia than expected in adult patients of four family practices in Netherlands.Ned. Tijdschr. Geneeskd. 2000; 144: 1437-1440
- Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.J. Clin. Endocrinol. Metab. 2012; 97: 3956-3964
- Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.Eur. Heart J. 2014; (First published online 28 Feb 2014)https://doi.org/10.1093/eurheart/ehu058
- Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia.Circulation. 1974; 49: 476-488
- Integrating provision of specialist lipid services with cascade testing for familial hypercholesterolaemia.Curr. Opin. Lipidol. 2010; 21: 366-371
- National Institute of Health and Clinical Excellence Clinical Guidelines and Evidence Review for Familial Hypercholesterolaemia: Identification and Management of Adults and Children with Familial Hypercholesterolaemia. 2008 (Clinical Guideline 71)
- Elucigene FH20 and LIPOchip for the Diagnosis of Familial Hypercholesterolaemia (NICE Diagnostics Guidance 2).2011
- Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: a systematic review and economic evaluation.Health Technol. Assess. 2012; 17https://doi.org/10.3310/hta16170
- An evaluation of DNA diagnostics for familial hypercholesterolaemia including a study of personal and family implications [abstract].Atherosclerosis. 2007; 194: 282
- Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.BMJ. 1991; 303: 893-896
- Familial Hypercholesterolemia - Report of a Second WHO Consultation.World Health Organization, Geneva, Switzerland1999 (WHO publication no.WHO/HGN/FH/CONS/99.2)
- Familial hypercholesterolaemia.in: Betteridge D.J. Lipids and Vascular Disease. Martin Dunitz, London2000: 65-76
- Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.Am. J. Cardiol. 1993; 72: 171-176
- The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.Atherosclerosis. 2005; 180: 155-160
- Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.Heart. 2013; 99: 175-180
- Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.Am. J. Cardiol. 2008; 102: 1187-1193
- Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH.Circ. Cardiovasc. Genet. 2012; 5: 354-359
- Multicenter study to determine the diagnosis criteria of heterozygous familial hypercholesterolemia in Japan.J. Atheroscler. Thromb. 2012; 19: 1019-1026
- Practice Guidelines for the Evaluation of Pathogenicity and the Reporting of Sequence Variants in Clinical Molecular Medicine.(Approved September 2013) Association for Clinical Genetic Science (ACGS), Dutch Society of Clinical Laboratory Specialists (VKGL), 2013
- A simple sequentially rejective multiple test procedure.Scand. J. Stat. 1979; 6: 65-70
- Interpreting diagnostic accuracy studies for patient care.BMJ. 2012; 2: 345-399
- Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.J. Mol. Med. 2006; 84: 203-214
- Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2654-2660
- Molecular characterization of familial hypercholesterolemia in Spain.Atherosclerosis. 2012; 221: 137-142
- Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting.J. Am. Coll. Cardiol. 2008; 52: 1546-1553
- Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis.Atherosclerosis. 2009; 207: 311-317
- Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.Atherosclerosis. 2013; 227: 342-348
- Diagnosis and screening for familial hypercholesterolaemia: finding the patients, finding the genes.Ann. Clin. Biochem. 2006; 43: 441-456
- Corneal arcus, case finding and definition of individual clinical risk in heterozygous familial hypercholesterolaemia.Clin. Genet. 1998; 54: 497-502
- Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.Lancet. 2013; 381: 1293-1301
- Development of sensitive and specific age- and gender specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.Clin. Chem. Lab. Med. 2008; 46: 791-803
- Diagnosis of heterozygous familial hypercholesterolemia DNA analysis complements clinical examination and analysis of serum lipid levels.Arterioscler. Thromb. Vasc. Biol. 1992; 12: 584-592
- Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.Semin. Vasc. Med. 2004; 4: 75-85
- Guidelines for the Diagnosis and Management of FH.The Cardiac Society of Australia and New Zealand, 2013
Article info
Publication history
Published online: March 06, 2015
Accepted:
March 5,
2015
Received in revised form:
February 15,
2015
Received:
October 28,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
