Facilitating genetic testing after death: the ongoing duty of care to the deceased and their relatives

Aim

To highlight the short window of opportunity for storage of tissue or DNA after someone has died. For health professionals working with families where there might be a genetic condition, this can be useful to make or refine a diagnosis in the deceased, and potentially enable predictive and preventative medicine for surviving biological relatives.

Case vignette: part 1

A 28-year-old woman had a telephone consultation with her general practitioner (GP). She was distressed following the recent death of her 35-year-old brother. He had been found dead in bed a week previously, and the cause of death identified on post-mortem examination was aortic dissection. Their mother had died suddenly in her late 30 s from ‘aortic rupture’; there was no other family history of aortic disease known but the mother had been adopted and had no information about her biological relatives.

The woman was now very concerned about her own risk of aortic rupture, especially as she was 20 weeks pregnant. She was also concerned about the risk to her unborn child, as well as her surviving brother and her late brother's children. Her father had approached her saying the post-mortem findings in her brother ‘might mean something for you’ but had not given any details about his contact with the coroner. The family all live near one another.

When the GP contacted the regional Clinical Genomics service for advice, the Consultant Clinical Geneticist realised that she had advised a Forensic Pathologist on the same case days previously.

Introduction: genetic testing in the deceased and its challenges

Such a scenario is seen with increasing frequency in regional Clinical Genomics services that are part of the NHS England Genomic Medicine Service. ¹ However, the question of whether there is a genetic diagnosis in someone who has died, and whether it might be relevant to a living relative, can present to any doctor.

The family member who presents with the clearest ‘phenotype’ (clinical features suggestive of a genetic disease) is the best person to offer genetic testing to as this makes interpretation of the ‘genotype’ (results of genetic testing) easier: a strong ‘genotype–phenotype correlation’ gives a more robust genetic diagnosis. Often, this will be the ‘proband’ in the family: the person who presents first with clinical features for assessment.

When the proband is deceased, post-mortem genetic testing can determine whether they carried pathogenic (‘disease-causing’) genetic variant(s) that caused or predisposed to a specific health problem. It can also be a means of helping to determine the cause of death, with genetic testing targeted by findings on post-mortem examination and the clinical history. As in life, the results of post-mortem genetic testing may be helpful for biologically related family members. They could be offered testing to establish whether or not they carry the same pathogenic genetic variant. This may enable screening, risk reduction, or reproductive options such as prenatal diagnosis and pre-implantation genetic diagnosis.

With advances in genetic technologies, it is now urgent that health professionals realise that refinement of a diagnosis in a deceased person can provide significant benefits to living relatives. In the case described, the cause of death could be a ‘sporadic’ aortic dissection, but, given the family history, identifying a genetic cause for the dissection can ensure healthy family members, who are subsequently identified as carriers of the familial pathogenic genetic variant (predictive medicine), are offered surveillance and management and might avoid life-threatening complications (preventative medicine).

Another challenge is ensuring that clinicians are aware of the basic practicalities of such genetic testing and that they act promptly, given the short window of opportunity to ensure the necessary steps are taken when this situation arises.

Highlighting these issues for all clinicians to ensure that post-mortem diagnosis of genetic disease can happen is therefore vitally important.

When to consider genetic testing in the deceased

For some specialties, post-mortem genetic testing is already part of routine healthcare. The regularly updated NHS National Genomic Test Directory (found here https://www.england.nhs.uk/publication/national-genomic-test-directories/), which lists clinically available Rare and Inherited Disease genetic testing by specialty, as well the testing criteria for each condition, is a useful resource for others to familiarise themselves with the extent of NHS genetic testing now offered. ² The risk to family members depends on the inheritance pattern of a given condition, and not all conditions have surveillance or specific management options.

As a general guide, circumstances when genetic testing in the deceased may be indicated are:

sudden death with no established cause;

aortic enlargement or rupture;

dilated or hypertrophic cardiomyopathy;

early-onset of a condition typically associated with older age, for example, neurodegenerative disorders or cancer.

A known family history of a condition may heighten the suspicion of a genetic diagnosis and thus strengthen the case for post-mortem investigation. When in doubt, regional Clinical Genomics services can be consulted.

Practicalities of genetic testing in the deceased

Obtaining a sample when someone has died suddenly, and the coroner is involved

Medical doctors and the police report deaths to the coroner, but anyone can if they have concerns. ³ A coroner must investigate deaths in certain circumstances, including when the cause is unknown. ⁴ The coroner may request that a post-mortem examination is carried out by a pathologist to determine the cause of death. ⁵ Consent is not required from relatives for post-mortem examination and removal and storage of tissue when under the coroner’s authority.^6,7

The pathologist must notify the coroner of any material retained and why. The coroner then advises how long the material must be kept, and passes information about the retained material to relatives, advising them of their options for it: lawful disposal, return to relatives, or retention with appropriate consent for use for purposes set out in the Human Tissue Act (HTA) 2004, once the authority of the coroner has ended. ⁸ Box 1 notes issues related to police involvement.^9–13

Ideally, immediate genetic testing would happen as part of the coronial post-mortem investigation as an extension of establishing cause of death, or refinement of a presumed diagnosis. If this does not happen, but a genetic condition is suspected, it is important that the family is advised by the coroner of the option for removal of tissue (this includes blood ¹⁴ ) for DNA extraction and storage, to enable possible future genetic testing. At a time of grief, highlighting the potential benefits of such genetic testing in explicit terms (the aim to prevent another family tragedy) may be helpful.

Box 1.

Police involvement.

If the police are involved and there is a criminal investigation, a Home Office-registered Forensic Pathologist may be requested to perform the post-mortem examination by the coroner. 9 If the deceased is a child, the Forensic Pathologist should follow a joint post-mortem examination protocol with a Paediatric Pathologist. 10

Material from the deceased, retained for the functions of a criminal investigation, is subject to police legislation.11,12

The police decide whether or not the material should be retained and will offer it to the coroner for the purposes of their investigation. 13

Box 2.

Considerations for genetic testing of DNA stored before death.

Is it part of good clinical care, for example, establishing a genetic diagnosis in a family member in order to offer predictive testing to unaffected relatives?

Is there is any reason to believe that the deceased person would not have wanted their stored DNA used in this way?

Does a relative want the deceased’s stored DNA used in this way?

Are there any other close relatives who might have an interest in knowing the plan for genetic testing and the result?

This also draws attention to the point that when the coroner is no longer involved, the person communicating the offer of retention of tissue with a view to genetic testing in future (including, for example, a non-medical coroner’s officer) needs to have training and expertise in taking consent in such circumstances. A family information leaflet, which explains the purpose and value of post-mortem genetic testing may supplement this.

For neonates, infants, and children up to the age of 18, there is specific additional regulation. The Children Act 2004 lays down the statutory duty to investigate the death of any child, ¹⁵ and the Kennedy Protocol (2016) ¹⁰ is the multi-agency guideline for such an investigation when the death is sudden and unexpected. The protocol lists suggested samples to be routinely taken immediately after death for infants and younger children. Although blood for chromosomal studies (lithium heparin sample tube) is listed, blood for molecular (DNA) genetics or DNA storage (both EDTA sample tube) is not. ¹⁰ We suggest this is now out of date, and that DNA-based genetic testing should be offered in a sudden unexplained death if criteria set out in the NHS National Genomic Test Directory are met. ¹⁶

When there is an ongoing pregnancy, as in the case vignette, a prompt decision about genetic testing may help manage potential complications during pregnancy via specialist input. At other times, advice on reproductive options may be appropriate prior to or in the early stages of a pregnancy. In these scenarios, the regional Clinical Genomics service can provide assistance.

For other conditions, the benefits of genetic testing may be less clear, for example, neurodegenerative disease where there may be no interventions to offer as a result of diagnosis. However, understanding of at least some of these diseases is advancing, as are developments in therapeutic research. ¹⁷ Explaining to the family of the deceased that the decision about genetic testing can wait until the situation is more settled for them, and that for now only a decision about DNA storage is required while there is an opportunity to do so, might make this easier.

What samples to take and store

Tissue itself, for example, spleen, can be stored for future genetic testing but this requires ultra-low temperature. DNA extracted from tissue (including blood) is best for long-term storage because it is stable and can be stored at more energy-efficient temperatures. ¹⁸ Nevertheless, resources are required (extraction facilities, storage space, security and expertise), which for NHS England are provided by Clinical Scientists working in Genomic Laboratory Hubs. ¹⁹ This means that indiscriminate storage of samples from the deceased is not advisable. Input from Regional Clinical Genomics services can be helpful in deciding whether potential benefits for the family warrant storage in a particular case.

When the coroner is not involved

Thinking about DNA storage can be equally important when a death is not under the authority of the coroner if an underlying genetic diagnosis is suspected. This may involve a hospital post-mortem examination that can be offered under certain circumstances when the cause of death is known, and a Medical Certificate of Cause of Death has been issued. ²⁰

For example, structural abnormalities detailed on post-mortem examination of a fetal death or termination before 24 weeks of pregnancy, which are suspected to have a genetic cause. The law considers fetal tissue to be part of the mother, ²¹ and so the coroner is never involved. In such cases, storage of tissue for potential future DNA analysis is important to try to find the cause of the abnormalities since identifying a genetic diagnosis may make it possible to advise on the chance of future pregnancies being affected in the same way. This is also important for stillbirths (delivered after the 24th week of pregnancy not breathing or showing any other signs of life), which also do not come under the coroner’s jurisdiction ²² but must be formally registered. ²³

Hospital post-mortem examination, and storage and use of tissue (including when the authority of the coroner has ended), are regulated by the HTA 2004.^24–26 The Act recognises the potential benefit of DNA analysis for family members and distinguishes between ‘analysis of cellular material’ (which may provide more detailed phenotyping which assists genotyping) and ‘analysis of DNA in cellular tissue’. If consent was not given in life, both of these, along with the hospital post-mortem examination, require consent from someone from a list of legally defined individuals (those is a ‘qualifying relationship’). The list is the same for all three, but for hospital post-mortem examination and analysis of cellular material, the list is ranked and the person highest on the list should give consent where possible. This is usually a spouse or partner. For DNA analysis of cellular tissue, the list is not ranked: anyone listed can consent. ²⁷

It may be helpful to encourage bereaved relatives who are highest on the list of consent, and who may not be biologically related, to consider when and how post-mortem findings may be relevant to biological relatives. Regional Clinical Genomics services can usually support such communication, especially with relatives who may not be aware of their risk.

Samples collected and stored during life

When someone has died and no post-mortem examination takes place, genetic testing may still be possible if tissue or DNA was stored while they were alive.

Stored tissue

In life, investigation and treatment of suspected cancer will often result in the routine storage of tissue as part of a person’s medical care. Such samples are stored with the consent of the person from whom they are taken, and this remains valid even if they subsequently die (that is to say, the rules for tissue taken before death are different from those taken after). Investigation of such stored tissue can be very helpful when relatives seek a genetic diagnosis for their family history, although it may be difficult to extract usable DNA from the tissue, for example, if it has been formalin fixed.

Stored DNA

If DNA was stored in life, the question of how genetic testing can proceed if the person then dies must be considered. Importantly, analysis of stored DNA is not covered by the HTA 2004, since it is not cellular material or tissue. ²⁸ Any relative can provide consent to analyse stored DNA if it might help inform their management, and this consent does not need to be in writing. To ensure such testing complies with the common law and professional guidance around consent and confidentiality, ²⁷ there are some important considerations. Some of these are listed in Box 2.

Clinicians can approach their regional Clinical Genomics service for guidance on how to arrange genetic testing for both ante-mortem stored tissue and DNA.

If an inherited condition is suspected, consider storing DNA in life even if current testing has not found an explanation

This might happen in a neurology clinic or general practice, where a patient is seen for issues relating to their neurodegenerative disease, and their family history of the same is noted. In the past, there may have been no or very few genes to test. But diagnostic genetic testing is improving and being able to access a stored sample may mean a genetic diagnosis can be made in future, even after death.

Case vignette: part 2

The Consultant Clinical Geneticist advised the Forensic Pathologist to ensure DNA was stored from the deceased brother and then asked the laboratory to activate aortopathy gene panel genetic testing.

The GP was advised to refer the pregnant 28-year-old woman urgently to the Clinical Genomics service. She was assessed, provided a detailed family history and a sample of her DNA was stored in the local laboratory. She was also referred urgently to a Consultant Cardiologist for cardiovascular imaging and surveillance during pregnancy.

Genetic testing for her deceased brother was expedited because of the pregnancy.

Written advice for other living first-degree relatives (siblings and children) of the deceased brother to be referred to a local Consultant Cardiologist was distributed by the father.

Six weeks later, a diagnosis of Marfan syndrome was confirmed on genetic testing in the deceased brother.

The pregnant woman and other first-degree relatives were tested for the pathogenic genetic variant identified. It was not detected in her and no further surveillance was necessary, but it was detected in other relatives for whom ongoing cardiovascular surveillance was arranged.

Conclusion

Making a genetic diagnosis in someone who has died can have a significant impact on the healthcare of their family. With advances in, and mainstreaming of, genetic testing, it is anticipated that most clinicians will be involved in genetic testing in future. ²⁹ This provides novel opportunities for genetic diagnoses if we routinely consider whether a patient’s presentation, in life or death, might have an underlying genetic cause, and arrange storage of appropriate samples for immediate or future genetic testing. Clinical Genomics services can help with this process and ensure that decisions are made in a timely fashion.

We recommend good communication between coronial and health services to ensure DNA is appropriately stored, so that families can be supported and advised correctly and promptly. This communication should extend to the steps after a sample has been stored, so that future testing is possible for relatives who come forward at a later date. Clinical Genomics services are well placed to liaise between all those involved when genetic disease is suspected in a deceased family member.