Update on rare diseases and genomic testing in primary care

Ivy Gao is a 2nd Year Biology Student at Imperial College London.

Kiran Jani is a Consultant Anaesthetist and Trustee for UK Clinical Ethics Network, Hertfordshire.

Chantal Patel is an Associate Professor and Head of Inter-Professional Studies at the University of Swansea.

Christine Oesterling is a GP at Eastmead Surgery, Greenford, and Senior Research Fellow at Imperial College London.

Adrian Tookman is a Palliative Care Physician and Chair for Forgotten Patients, Overlooked Diseases Charity, London.

Steven Walker is Director for St Gilesmedical Ltd, London, a Tutor for the University of Applied Science, Bremen, Germany, and Trustee and Secretary for Forgotten Patients, Overlooked Diseases Charity, London.

‘Is it bad genes, doctor?’ Recent medical news coverage has given hope to many people with complex undiagnosed health issues searching for the cause for their symptoms. Healthcare professionals (HCPs) are increasingly being asked to consider referral for genetic testing. While for the majority with an abnormal finding, curative treatment is not currently possible, having a disease with a name can bring relief and allow for more targeted supportive measures. Here we provide a brief update.

What are rare diseases?

It is likely that you will not be familiar with antiphospholipid syndrome (incidence 1–2 per 100 000) or Klippel-Trenaunay-Weber syndrome (1 per 20 000). These are both rare diseases, defined by the European Commission on Public Health as ‘life-threatening or chronically debilitating diseases … of such low prevalence that special combined efforts are needed to address them’.1 ‘Rare’ usually implies a disease frequency under 1:2000 individuals; collectively they affect 3.5%–5.9% of the global population.2

“It is estimated that 80% of rare diseases have a genetic basis.”

It is estimated that 80% of rare diseases have a genetic basis.3 Though the number affected by each disease is small, together they amount to a significant public health issue. An increasing proportion are being diagnosed during pregnancy or soon after birth due to a physical or biochemical abnormality detected during screening, for example, phenylketonuria (PKU) and cystic fibrosis.

By comparison, many adults will go through life never knowing that they carry a potentially harmful gene, while others first come to medical attention due to the onset of debilitating symptoms and premature death. By way of example, Huntington’s disease generally presents between the ages of 30 to 50 years with movement, thinking, and psychiatric disorders. Involuntary jerking or writhing movements are typical features (chorea). Death is generally 10–30 years later.

Due to recent advances in genomics, significant progress is being made in the management of rare diseases. For an increasing minority, interventions exist that could significantly improve quality of life and/or reduce complications. With over 7000 rare diseases currently listed,4 most GPs will lack experience in recognising or managing affected individuals. Hence, it can take years to reach a diagnosis and misdiagnoses are common.5 Delays can add to patient morbidity, increase stress for families, waste resources, and frustrate HCPs.

Advances in genomics

Many diseases with a genetic basis can initially be picked up by examining the gene product rather than the individual’s DNA because this is cheaper and more accessible, for example, looking for PKU using a heel prick test. By comparison, cystic fibrosis can only be reliably diagnosed in infants by genetic testing.

“… whole genome sequencing now tak[es] up to 15 hours and cost[s] less than £1000.”

The diagnostic landscape has been altered by research, such as the 100,000 Genomes Project, with whole genome sequencing now taking up to 15 hours and costing less than £1000.6 This trend is expected to continue with advances in bioinformatics to optimise data analysis and rapid next-generation sequencing (NGS) techniques.7

By comparing the genome of asymptomatic participants with individuals afflicted by rare various diseases,8 this work has helped hundreds of patients finally receive a diagnosis.9

Practical aspects in primary care

Approximately 50% of first trimester miscarriages are due to a chromosome abnormality in the foetus.10 In developed countries, many diseases caused by a genetic abnormality will already have been diagnosed before the patient is first seen in primary care. More than 30% of affected children die before their 5th birthday while others remain undiagnosed until recognisable features appear.5 Suspicion will likely be raised if there is a strong family history or the individual has dysmorphic features, multiple anomalies, unusual symptom complexes, or unexplained neurocognitive impairment.5 Genetic testing may be useful in selected cases after all the simple stuff has been done. It can, however, be challenging to organise with different eligibility criteria, forms to complete, and referral pathways depending on your location.

You may already be familiar with testing in cancer patients and their families. The practicalities of the test at the point of care are simple: a sample of the patient’s DNA is obtained via a blood or saliva sample. This is then sent to a specialised laboratory for analysis, with a result being available several weeks later.11 Genetic clinics are available throughout the UK providing testing and advisory services. A useful national resource is the British Society for Genetic Medicine website. Here, you will also find details of outreach and disease-specific clinics. Another useful initiative for clinicians is the QGenome app. Developed by Guy’s and St Thomas’ NHS Foundation Trust regional genetics service, a partner in the South East Genomic Medicine Service Alliance and UBQO, it provides free advice on how to refer, risk assessment, testing, and possible diagnoses.

Most genetic testing is targeted at identifying a particular gene or a panel of genes thought likely to be associated with a medical condition, susceptibility to disease, or drug reactions. For example, if the patient has fragile skin, then you may request the lab perform a connective tissue disorder panel. In some cases, the results will be inconclusive, and further testing will be required.

“For the GP, broaching the subject of genetic testing requires sensitivity.”

By comparison, routine sequencing of a person’s complete DNA looking for alterations (whole exome sequencing, WES) is rarely performed outside of research projects. Such assays produce large amounts of data that must be analysed and interpreted. For example, it can be challenging to determine whether a particular variant is clinically actionable.

A further issue is that while a genetic cause is assumed, the associated genes may not yet be known, for example, the most common type of Ehlers-Danlos syndrome (90%), Hypermobile EDS (hEDS) affecting 1 in 3100 to 1 in 5000 individuals can at present only be diagnosed on clinical grounds.

For the GP, broaching the subject of genetic testing requires sensitivity. Parents may, for example, come to regard their child as ‘abnormal’. Similarly, older subjects may worry about passing ‘bad’ genes onto their offsprings or how their partner will respond to this new information. In some unlegislated countries, data security, obtaining life insurance, and unrestricted health care will be a concern. Finally, some prospective employers may search social media accounts looking for evidence of chronic health issues. Despite the HCP’s best efforts and any help from local genetic counselling services, it is ultimately the patient and/or the parents’ choice on whether to undergo testing.

What happens next?

Following testing, the patient will generally be followed up by the regional genetic service. If a definitive diagnosis was made, then the patient will be referred to a specialist. Further management will usually involve assessing the severity of the patient’s condition, exploring any potential treatment options, and seeking advice from a counsellor. If the rare disease has a genetic basis, close relatives and any offspring may be offered testing to determine if they are at risk for the same disease.

“Often all that can be offered are symptomatic treatments, physio, and occupational therapy … “

While genetic testing may suggest the possibility of a specific therapy, high cost and time required for research and development mean that over 90% of rare diseases lack approved treatments.12 Often all that can be offered are symptomatic treatments, physio, and occupational therapy and lifestyle modification such as changes in diet (for example, restriction of phenylalanine in PKU) and exercise.

Most diseases will have an advocacy group. Here patients can usually find advice and support from affected individuals. A good starting point is to direct your patient to the Eurordis website, which provides links to over 1000 rare disease charities.

It is worth emphasising that treatment for rare diseases continues to evolve. For the fortunate few, increased investment has led to the establishment of schemes such as the Innovative Medicines Fund that can provide access to experimental treatments.13 Here, GPs may find themselves supporting specialist physicians in the applications process. Also, there is growing interest among academics and increasing commercial investment in the development of new treatments.12 Research costs can be huge and responsible companies can find themselves being criticised for profiteering as they try to recoup their investment.14

Definitive treatment

Should the underlying cause for a patient’s disease be due to a genetic abnormality, this does not mean that the treatment requires complex gene therapy. Type 1 Gaucher disease, a rare inherited metabolic disorder, for example, can be managed by regular injections of enzyme replacement therapy.

For some patients with a rare disease, a ‘cure’ is increasingly possible by altering the genes inside cells through introducing a functional copy of the responsible faulty gene(s) or directly replacing them by genome editing.

There are many challenges in delivering successful gene therapy. These include how to introduce the ‘new’ gene. A common technique is using a viral vector.15 These treatments currently only target somatic (non-reproducible diploid) cells due to concerns that there may be unintended consequences on future generations when editing germline cells. Therefore, offspring are still susceptible to inheriting a rare disease from their parents.

“… the Eurordis website … provides links to over 1000 rare disease charities.”

Previously, only a few gene therapies were approved for use, but recent advances in genomics are changing this. These include the development of tissue chips that can be used to test the effects of potential therapies before use in human trials,16 as well as better and more effective vectors, used to deliver functioning genes or gene-editing tools into cells.17

Adapted from a naturally occurring genome editing system used by bacteria as an immune defence, CRISPR (short for clustered regularly interspaced short palindromic repeats) is a widely used gene editing technique that employs small pieces of genetic code called guide ribonucleic acids (gRNAs) along with Cas enzyme, Cas9. In the CRISPR-Cas9 system, scientists design a gRNA to target a specific section of the DNA, directing Cas9 to the desired location. There, Cas9 initiates a break in both strands of the double-stranded DNA structure. The cell’s DNA repair machinery then repairs the cut, altering the DNA by randomly adding or deleting genetic material, potentially rendering a gene non-functional, or by precisely replacing an existing segment with a customised DNA sequence to introduce a gene.18

In conjunction with increased investment, these are leading to the development and utilisation of gene therapy for more rare diseases. For example, the NHS recently rolled out Libmeldy in 2022 for the treatment of metachromatic leukodystrophy (MLD).19 Other therapies approved recently include Roctavian and Zolgensma for haemophilia A and spinal muscular atrophy, respectively.

Is genetic testing worth doing even if there is no treatment?

Knowing is generally better than ignorance. The absence of a diagnosis brings challenges for the individual, their families, and HCPs entrusted with their care. Without knowledge of the disease aetiology, any available treatment options cannot be accessed. A diagnosis can prevent a cycle of frequent medical attendances, inconclusive tests, and unsuccessful, potentially harmful interventions. Unsurprisingly, management of such individuals comes with a high socioeconomic burden. People feel lost within the health system not knowing where to turn and are at risk of deterioration and mental illness. For those where a cure is not yet possible, they can still be assisted with a range of symptomatic treatments and supportive care.

“A diagnosis can prevent a cycle of frequent medical attendances, inconclusive tests, and unsuccessful, potentially harmful interventions.”


There are ethical and safety issues associated with the growing use of genomics. For instance, there are concerns that genome sequencing may be used to discriminate against certain individuals6 or that gene therapy could have unforeseen consequences.3 There is also the possibility of incidental findings during genetic testing that are unrelated to rare diseases but may have implications for the patient’s health. Should these be communicated to a patient? And what if it is an issue that may affect the patient’s relatives?

Equity of access to health care is a significant problem for many people worldwide due to their socioeconomic and ethnic background.6 As above, this may be exacerbated by the finding of a genetic abnormality with potentially higher costs for individuals, insurance companies, and employers. There are also ethical concerns related to rare disease treatments, especially regarding resource allocation. Allocating more resources to rare diseases could lead to trade-offs where treatment and care for more common conditions becomes less of a priority.14


Major advancements have been made in the management of people with rare diseases. Those affected are increasingly being diagnosed earlier and treatment options continue to expand. Genetic testing is becoming more prevalent in parallel with advancements in technology. All of this is likely to increase demand and the expectation of a cure. The latter will remain a distant dream for the majority. For those working in primary care, they will probably receive more requests for testing, while being increasingly required to co-manage a wider range of rare diseases and cope with ever more complex treatments. For our society, there remain unresolved ethical and socioeconomic considerations. We all need to watch this space.

We are grateful to Lylah Drummond-Clarke for genetic advice.

1. European Commission. Useful information on rare disease from an EU perspective. (accessed 15 Feb 2024).
2. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020; 28(2): 165–173.
3. Jackson M, Marks L, May GHW, Wilson JB. The genetic basis of disease. Essays Biochem 2018; 62(5): 643–723.
4. Ferreira CR. The burden of rare diseases. Am J Med Genet A 2019; 179(6): 885–892.
5. Department of Health and Social Care. The UK Rare Disease Framework. 2021. (accessed 12 Feb 2024).
6. Yu TW, Kingsmore SF, Green RC, et al. Are we prepared to deliver gene‐targeted therapies for rare diseases? Am J Med Genet C Semin Med Genet 2023; 193(1): 7–12.
7. Park ST, Kim J. Trends in next-generation sequencing and a new era for whole genome sequencing. Int Neurourol J 2016; 20(Suppl 2): S76–S83.
8. Department of Health and Social Care. 100,000 Genomes Project. (accessed 12 Feb 2024).
9. Smedley D, Smith KR, Martin A, et al. 100,000 Genomes Pilot on rare-disease diagnosis in health care — preliminary report. N Engl J Med 2021; 385(20): 1868–1880.
10. Hardy PJ, Hardy K. Chromosomal instability in first trimester miscarriage: a common cause of pregnancy loss? Transl Pediatr 2018; 7(3): 211–218.
11. NHS England. Whole genome sequencing for a rare disease: information for patients and family members. (accessed 12 Feb 2024).
12. Austin CP, Cutillo CM, Lau LPL, et al. Future of rare diseases research 2017–2027: an IRDiRC perspective. Clin Transl Sci 2018; 11(1): 21–27.
13. NHS England. NHS England announces new Innovative Medicines Fund to fast-track promising new drugs. 2021. (accessed 12 Feb 2024).
14. Ollendorf DA, Chapman RH, Pearson SD. Evaluating and valuing drugs for rare conditions: no easy answers. Value Health 2018; 21(5): 547–552.
15. National Human Genome Research Institute. Gene therapy. 2024. (accessed 12 Feb 2024).
16. Blumenrath SH, Lee BY, Low L, et al. Tackling rare diseases: clinical trials on chips. Exp Biol Med (Maywood) 2020; 245(13): 1155–1162.
17. Zu H, Gao D. Non-viral vectors in gene therapy: recent development, challenges, and prospects. AAPS J 2021; 23(4): 78.
18. Xu Y, Li Z. CRISPR-Cas systems: overview, innovations and applications in human disease research and gene therapy. Comput Struct Biotechnol J 2020; 18: 2401–2415.
19. NHS England. NHS to roll out life-saving gene therapy for rare disease affecting babies. 2022. (accessed 12 Feb 2024).

Featured photo by Warren Umoh on Unsplash.

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