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Familial hypercholesterolaemia: genetic testing in general practice and beyond
  1. Tom Brett1,2,
  2. Gerald Francis Watts3
  1. 1 General Practice and Primary Health Care Research Unit, School of Medicine, The University of Notre Dame Australia, Fremantle, Western Australia, Australia
  2. 2 General Practitioner, Mosman Park Medical Group, Perth, Western Australia, Australia
  3. 3 School of Medicine, Royal Perth Hospital, The University of Western Australia, Perth, Western Australia, Australia
  1. Correspondence to Professor Tom Brett, General Practice and Primary Health Care Research Unit, School of Medicine, The University of Notre Dame Australia, Fremantle 6160, Australia; tom.brett{at}

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Familial hypercholesterolaemia (FH) is a preventable cause of premature coronary artery disease and death, with significant potential impact on public health1 and meeting all criteria for screening for a condition. Early detection of FH rests on the premise that the burden of atherosclerotic cardiovascular disease due to genetically elevated low-density lipoprotein cholesterol begins at birth and accumulates over time, and that treatment in childhood prevents coronary events and reduces mortality.2

The public health importance of FH is also underpinned by knowledge that its prevalence is as high as 1:250.1 However, only 10% of people worldwide are currently recognised as having FH.2 A recent international global call to action3 has championed the need for improved screening and diagnosis.

To identify >90% of the population with FH requires multiple approaches, but integrating cascade testing of family members of index cases with some form of universal screening at younger ages may have the highest potential. Opportunistic, selective, systematic and universal screening strategies, employing phenotypic and genetic testing, are other approaches that are reported as cost-effective.2 More recently, whole population genetic screening has been proposed.

Genetic testing has several advantages: it improves precision of diagnosis and risk prediction, facilitates family counselling and cascade testing, and can improve adherence to therapy.4 General practice plays a key role in the detection of FH for several reasons, including ease of access to services, a preference for patients to receive treatment locally and awareness of intergenerational conditions in families. A key goal of the WHO is to focus on primary healthcare to facilitate easy and equitable access to quality health services.5

Recent study

The study by Qureshi et al 6 offers a new approach to increase primary care involvement in diagnosing FH by offering FH genetic testing through general practitioners (GPs) for patients with likely phenotypic criteria.

The investigators applied a novel case finding tool (Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT1)) to interrogate the electronic health records (EHRs) in the study practices and identify those at increased risk of FH. A total of 44.5% of patients aged 18 years and above had lipid profiles available. Both FAMCAT and TARB-Ex are data extraction tools used in primary care to rapidly screen EHRs to identify those at highest FH risk. FAMCAT1 has been modified to enable EHR review without the need for subsequent manual record review.

A cohort of 336 adult patients with at least a possible risk of FH, who consented to completing a family history questionnaire plus a detailed review of their clinical records, were subsequently offered genetic testing, involving next-generation sequencing. A total of 26 (9%) out of 283 patients tested were found to be either genetically positive (n=16) or to have ‘variants of uncertain significance’ (VUS) (n=10) and were referred to a lipid specialist with 19 out of 26 attending. A further 153 patients (54%) had ‘polygenic hypercholesterolaemia’ and were managed in primary care. The remainder were given heart healthy advice.

Study limitations

The mutation detection rate was low, with no estimate of cost-effectiveness. The study did not address detection in children, cascade testing of close relatives or the role of other genetic cardiovascular disease risk markers, for example, Lp(a).

Another potential limitation concerns the value of knowing about ‘polygenic hypercholesterolaemia’. The management of patients (54%) with ‘polygenic hypercholesterolaemia’ remains unclear, despite suggestive evidence that at least in the setting for frank FH such a finding may confer increased risk of coronary artery disease. Without clear demonstration of their cost-effectiveness, genetic analysis and reporting of cholesterol and coronary artery risk scores remain of interest to researchers alone.

Study strengths, novelty and future roles for general practice

The clinical approach employed was acceptable to patients. The investigators noted that regular cholesterol testing and monitoring is currently established practice in primary care and having a blood test to confirm a genetic diagnosis was acceptable. Genetic testing in general practice could potentially refine the referral pathway to lipid specialists with only the genetically positive or those with VUS referred to specialist care. Such a pathway could help reduce the expense and workload of tertiary hospital clinics.

Some of the biggest gaps in the detection and management of FH are among children and adolescents and in primary care.1 2 4 To effectively integrate GPs into providing comprehensive screening to help identify FH among their everyday patients, there is an urgent need to address their current lack of awareness about FH and then progress to improving their capacity and motivation to be involved in its management.

The novel aspect of the study is that genetic testing could be offered in general practice to patients with strong FH phenotypes who are willing to consent to genetic testing to achieve a precise diagnosis.7 8

An alternative diagnostic pathway, not proposed by the authors, could involve continuation of referrals to specialist clinics, but with a more rationed approach whereby mutation-positive, low-risk patients may continue management in general practice. This would particularly apply if cascade testing could be carried out with appropriate counselling support for close relatives (first and second degree). It remains to be established whether general practice is able and ready to assume this role.

How the study can improve practice

Increased GP upskilling and knowledge of basic genomics will be needed both for a counselling and advisory role in the benefits of early diagnosis and treatment,4 7 especially to inform other family members with most to gain from such management. Making a precise genetic diagnosis7 8 offers the opportunity for primary prevention among younger family members by preventing the progression of atherosclerosis in coronary arteries and subsequent myocardial infarctions and angina later in life.2

A history of premature coronary disease in close relatives should encourage GPs to undertake cholesterol testing in children and adolescents.4 If a family member has a positive genetic mutation, it is essential their close relatives including children are offered genetic testing. Confirmation of a genetic mutation in heterozygous children allows for the introduction of lipid-lowering statin therapy from the age of 8 years (or earlier in homozygotes) coupled with diet and exercise advice and avoidance of smoking.4

The potential for whole population genomic testing has recently been proposed, but remains untested. As this foresees integration of genetic screening with primary care, risk reduction pathways will be essential. It is noteworthy also that the absence of a pathogenic mutation does not exclude a diagnosis of FH and that current knowledge of all possible mutations is incomplete.2 Can GPs handle such diagnostic uncertainty?

General practice role in FH diagnosis and management

Experience worldwide tells us that the best and most efficient healthcare systems are built on a solid base of excellence in primary healthcare. While the potential role of general practice in the detection and management of FH is encouraged,2 4 the infrastructure to allow it to function in a meaningful, cost-effective and cost-efficient way does not currently exist. Qureshi et al 6 offer a potential new role for general practice, providing genetic testing for patients with likely FH and then progressing to management in a shared care arrangement with lipid specialists.

Future shared care model

Patients at lower risk and those with a preference for their GP to undertake genetic cascade testing could be managed in general practice. This will involve increased awareness education for GPs, patients and families about FH diagnosis and management. In addition, adequate training in genomic medicine including supportive counselling skills for GPs undertaking genetic testing could usefully be embedded in healthcare systems including a triage model to optimise care needs (figure 1).

Figure 1

Ascertainment tool. CVD, cardiovascular disease; FH, familial hypercholesterolaemia; GP, general practitioner; HeFH, heterozygous FH; HoFH, homozygous FH; LDL-C, low-density lipoprotein-cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; VUS, variant of uncertain significance, *Refer to Sturm et al 7 and Brett T et al 9. DLCNC, Dutch Lipid Clinic Network Critieria; FAMCAT1, Familial Hypercholesterolaemia Case Ascertainment Tool.

Currently, cascade testing has leaned towards a coordinated, centralised approach, but the ideal model for general practice needs implementation science to define and achieve its potential. All new genetically confirmed patients with FH should be included in an FH Registry to monitor their treatment and linkages to relatives. A new approach, possibly involving some form of universal screening in youth combined with reverse cascade testing or even population-based genomic testing, will be needed. But does this raise the spectre of general practice biting off more than it can chew? It is unlikely to be the last piece in the jigsaw.

Ethics statements

Patient consent for publication


Thanks to Dick Chan for help with the development of figure 1.



  • Contributors TB is the lead author on the submitted editorial. GFW is the coauthor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests TB has received NHMRC Partnership grant funding (GNT1142883) for research into familial hypercholesterolaemia. The WA Health Department provided partner funding for the study. Both Sanofi and Amgen were also partners in the study. GFW was also a CI on the study and has received honoraria for lectures, advisory boards or research grants from Amgen, Arrowhead, AstraZeneca, Esperion, Kowa, Novartis, Regeneron and Sanofi.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; externally peer reviewed.

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