Recommendation 2

Recommendation 2. Facilitate timely and accurate diagnosis as a rare disease diagnosis can lead to better clinical care, peer support, reproductive confidence, and access to services and clinical trials.

Recommendation 2.1

Identify red flags that indicate someone may have a rare disease.

Why this is important:

Around 2 million Australians have a rare disease and diagnostic delay is a major challenge for this population, with:

• Many people waiting an average of 5–7 years for a diagnosis, if one is ever made
• 4 out of 10 people living with rare disease in Australia reporting seeing more than six doctors and having at least one misdiagnosis.⁵⁰

“My diagnostic odyssey took 56 years. I have multiple organ damage and left the job I loved due to illness. I receive no government support and my medical costs are high. If diagnosed and treated earlier, I would still be working, not so ill and having a much better quality of life!”

How to progress Recommendation 2.1:

Consider rare disease when diagnosing new and existing patients. This can be done by taking a family history, carefully reflecting on people’s key clinical signs and symptoms, and listening openly to their concerns and suggestions.^9,51 It is important to recognise that rare diseases are often complex and involve multiple organ symptoms. Carefully review a person’s current and previous medical history and be open to the possibility of connections between symptoms that at first may seem unrelated.

The ‘Family GENES’ mnemonic was developed by the Genetics in Primary Care Faculty Development Initiative (based in the USA) to help clinicians recognise when a person might have a genetic condition.⁵² This tool can be adapted to the rare disease setting (Figure 3). It helps signpost when a referral to a diagnostic centre should be considered (Appendix 2.10a). It especially highlights the importance of being open to the possibility of connections between at first seemingly unrelated issues.

Figure 3: Family GENES tool. Adapted from the Genetics in Primary Care Faculty Development Initiative.⁵²

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Recommendation 2.2

Follow established protocols and pathways for timely and accurate diagnosis.

Why this is important:

International experts recommend that all people with a suspected rare disease should receive a diagnosis within 1 year if they have a condition known in the medical literature,⁵³ to facilitate access to optimal management, treatments, supports, and if appropriate, genetic counselling.

“I was ill for 20 years before I was offered genetic testing–I didn’t know this was part of the protocol. If I know why certain tests are being done (and the frequency of them) or why they have stopped looking for answers, I think I would feel less confused about my disease management.”

How to progress Recommendation 2.2:

Instigate or refer people suspected of having a rare disease to appropriate diagnostic testing. This may be to the relevant specialty if symptoms are isolated to one body system, or to a rare disease Centre of Expertise or clinical genetics service if they are multisystem disorders. In time, information on Centres of Expertise will be available on the RARE Portal (Appendix 2.2).¹¹ A list of clinical genetics and metabolic services and up-to-date information on genetic tests and the informed consent process is provided by the Centre for Genetics Education (Appendix 2.2).⁵⁴ It is ideal to provide information about waiting times for such services, as these can be significant and often currently exceed 1 year.

Search engines such as PubMed⁵⁵ and Online Mendelian Inheritance in Man (OMIM)⁵⁶ may be helpful in constructing a differential diagnosis to help guide appropriate diagnostic testing or referrals. A growing number of search engines (Appendix 2.10b) incorporating artificial intelligence can be used to help diagnose rare diseases, such as the Orphanet Clinical Signs and Symptoms App,⁵⁷ Find Zebra,⁵⁸ and PubCaseFinder.⁵⁹ These list potential underlying conditions and/or genetic causes based on the phenotypic information entered (that is, observable characteristics).^60-62

Diagnostic tests will vary based on a person’s symptoms. Given that approximately 80% of rare diseases have a genetic basis, familiarity with genetic and genomic testing processes, which Medicare item numbers are available to fund genomic testing for what indications, and the informed consent processes is needed, with many educational resources on these topics provided by the Centre for Genetics Education (see Appendix 2.2).^54,63 Lesson 5 of the Rare Disease 101 Australia e-learning module (see Appendix 2.2) covers diagnosis and diagnostic tools, including examples of using the Family GENES mnemonic and rare disease search engines.⁶⁴

Genetic and genomic testing is becoming more widely available in Australia, and is funded or subsidised under Medicare in several clinical situations. Diagnostic yield varies and can improve over time as new genes are discovered and technology improves. Re-testing or re-analysis of previous genetic or genomic testing results is an option that can be discussed with people who remain without a diagnosis. Moreover, as discussed in more detail below, referral to an undiagnosed disease program can be considered.

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Recommendation 2.3

Support people living with rare disease who remain on the diagnostic odyssey.

Why this is important:

It is estimated that a diagnosis explaining all symptoms cannot be made for at least half the people assessed by health professionals as being likely to have a rare disease. This may be because the causative condition cannot be identified, due to challenges in recognising the full spectrum of clinical features associated with individual rare diseases, or because the rare disease is not yet discovered.⁶⁵

People living with an undiagnosed rare disease cannot be provided with an accurate prognosis, and have little access to evidence-based treatment, Centres of Expertise, clinical trials, or patient advocacy groups. Moreover, a lack of diagnosis can be a roadblock to obtaining adequate funding from the NDIS.⁹

Remaining on the diagnostic odyssey can also have significant impacts on people’s mental health and wellbeing. People living with rare disease may feel uncertainty, stigma, and frustration, especially if they perceive health professionals do not believe they have a real condition.^50,66,67

“We have had to fight the entire length of our journey to ensure our daughter was diagnosed in a reasonable time frame, follow up and chase care and information. If you do not have the ability to do this, you get left behind and lost in a complex world of rare care.”

How to progress Recommendation 2.3:

Identify which people in your practice have a suspected but undiagnosed rare disease and implement the following five steps.

1. Provide person centred symptom-based care. Even without an aetiological diagnosis, it is possible to practice integrated care based on a person’s symptoms and their priorities for their own health care (see Recommendation 1). Where possible, people living with rare disease can be offered referral to Centres of Expertise for the group of conditions most closely aligned with their symptoms.
2. Screen for mental health and wellbeing and facilitate appropriate supports. Due to the uncertainty inherent in living without a diagnosis, the mental health and wellbeing of people living with rare disease should be carefully considered in each appointment. Those who are undiagnosed may have a greater need for referral to mental health services and care navigation than people with a diagnosis (Recommendation 5).⁶⁸
3. Facilitate practical and financial supports. Practical supports such as the NDIS can still be accessed by people living with rare disease, and health professionals can play an important role by providing letters of support that delineate the impact of a person’s symptoms. It is also important to check whether people with rare disease, including family members and carers, are accessing the full range of financial support benefits that they are entitled to. The Disability Support Information section on the RARE Portal includes information to help navigate current disability, carer and aged care supports and financial entitlements (Recommendation 6).⁶⁹
4. Connect to support groups for undiagnosed families. Providing information on specific support organisations such as Syndromes Without A Name (SWAN) Australia⁷⁰ and, internationally, the Wilhelm Foundation⁷¹ can help people with an undiagnosed rare disease access further supports (Recommendation 4; Appendix 2.11).
5. Offer connection to undiagnosed disease programs. Lastly, it is important to discuss a referral back to a clinical genetics service to review previous testing and see if more up-to-date testing may be helpful if an underlying genetic cause for a rare disease is considered. Genetics services can also help families who want to explore research diagnostics including undiagnosed disease programs (UDP). UDPs like the Australian Undiagnosed Disease Network (UDN-Aus)⁷² and the Undiagnosed Diseases Network International (UDNI)⁷³ offer opportunities for clinicians to enrol undiagnosed families in cutting-edge clinical research (Appendix 2.12). This research boosts diagnostic yields by applying genomic reanalysis, international case ‘matchmaking’ and multi-omic tools such as RNA sequencing.⁷⁴ Some states also have UDPs that run as clinical services and partner with the UDN-Aus research network (Appendix 2.12).

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