Rare disease genomic testing: promoting timely and equitable access

Equitable access to timely genomic testing for people affected by rare diseases is essential to provide an accurate diagnosis for patients and families to understand the cause of their own or their child's symptoms and to inform key clinical decisions and care management.

A recently published Position Statement by the Association for Clinical Genomic Science Rare Disease Position Statement Working Group describes best practice guidance for the specialist genomics workforce within the national health services in the UK and Ireland. Setting out these comprehensive guidelines covering the end-to-end process of genetic testing allows patients to understand what they can expect from the service. The guidance includes recommendations to facilitate equitable and consistent delivery of services for patients and families wherever they reside across the UK or Ireland.

The Position Statement describes eight fundamental requirements with a set of recommendations relating to laboratory practice (maximising efficiency and diagnostic yield), consistent compliance with national guidelines, service development and improvement which has been informed by patient experience involvement, management of service demand and capacity, workforce, and education and training for service users.

A key component in the development of this guidance was the recognition that to deliver the highest quality diagnostic genomic testing efficiently and effectively that meets the needs of the population, all stakeholders had to come together, including the people for whom the service is there to serve: the patients and families. The patient organisations, Unique and Genetic Alliance UK, were brought onboard from the earliest stage.

Implementing a service where the perspectives of the patients and families accessing and navigating rare disease testing pathways are sought and included to inform service delivery and improvement will maximise patient benefit.

A one-day workshop was convened by the UK Association for Clinical Genomic Science to share best practice and develop the position statement. The meeting was attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute.

Delivering an efficient and effective service within a nationalised healthcare system requires careful balancing of resources to ensure that the people most in need can access appropriate genetic testing. Testing not only needs to be both equitable but also to be delivered in a timely manner. It is vital that turnaround times for patients at all stages of the process are monitored and managed including access to the genomic test itself, receiving the test results (in an appropriate fashion from an appropriate clinician) and follow up and referral (where necessary).

Waiting times at each stage should meet the national standard and be consistent throughout the service to ensure equity for the whole population. Interpretation of genomic data requires a highly skilled workforce and a well-developed data infrastructure. Adherence to national guidelines regarding annotation, interpretation and reporting of results together with comprehensive phenotyping to ensure the right patients are accessing the right genomic test will minimise the chance of misdiagnosis (where the genomic result does not match, or is unlikely to account for, the phenotype) or missing a diagnosis.

In recent years, much work has been undertaken with all stakeholders, including the views and perspectives of patients, to determine appropriate reporting of results such as incidental findings and variants of uncertain significance. This work has resulted in Best Practice guidelines from the British Society for Genetic Medicine and the Association for Clinical Genomic Science which have been developed to minimise potential harm and confusion for patients by reporting only those results which are most likely to have clinical and personal utility.

Clinical eligibility criteria for genomic testing enable resources to be appropriately targeted at patients and families who are thought likely to be affected by rare genetic condition and in whom a diagnosis will guide clinical management and personal decision-making. It is also important to recognise that testing patients in whom there is a very low likelihood of identifying a genetic diagnosis can cause harm through unnecessary anxiety and a higher likelihood of producing uncertain results and misdiagnosis.

Advances in genomic testing means that a genetic diagnosis is found for an increasing number of rare disease patients, but there are many reasons why a genetic diagnosis may not be found. An estimated 50 percent of patients who undergo genomic testing will arrive at the end of the testing pathway without a diagnosis.

It should be clear to the patients and those caring from them, that many of these people who remain without a reported genetic diagnosis, will in fact have an underlying genetic cause for their features or symptoms – it has just not been possible to find it with current knowledge and technology available. Inevitably this leads patients and families to think about reanalysis of their genetic data and/or further testing.

It is crucial that patients and families understand when and which genomic data will undergo routine reanalysis. It is also important that there are clear and transparent processes that define the rationale and eligibility for further testing and the clinical circumstances where reanalysis of data should be considered.

Technology advancements, scientific discoveries and reanalysis continue to result in new diagnoses for some patients and families, as exemplified in the recent discovery that variants in the RNU4-2 gene have been shown to be a common cause of a neurodevelopmental disorder.

RNU4-2 is a 'noncoding' gene, a rarer type of gene that does not code for a protein. Such noncoding genes were not included in earlier genomic tests, either because the noncoding DNA was not sequenced in the test, or the gene was not analysed because there was no evidence to link it to a rare disease.

However, it is equally vital that families do not feel that they have been left in limbo, waiting for a diagnosis to be imminently delivered, and to reassure them when they have had all the appropriate genomic testing and analysis, allowing them to make decisions and move forward with their lives. Whether an underlying genetic cause has been found or not, it is vital that rare disease patients and families receive equitable and appropriate clinical care and support.

The overarching objective of these guidelines is to facilitate high quality diagnostic genomic testing delivered efficiently and effectively within a clinically relevant timeframe as part of a robust, patient-centred service.