The era of genomic medicine has been transforming the clinical care of patients in mainstream medicine. Next generation sequencing (NGS) on whole exome platforms is soon to be phased into whole genome platforms, now that the piloting of the 100,000 Genomes Project (www.genomicsengland.co.uk) is coming to an end. It has enabled more accessible genetic tests than ever.
The genetic testing landscape has changed dramatically in the last decade: from single gene tests, moving on to panel gene tests and recently on to agnostic trio whole exome, and now genome, sequencing. This is a time of unprecedented increase in knowledge of the genetic basis of disease against a background of rapidly changing technology, and has been translated into the highest diagnostic rate for hereditary disorders in medical history. It is therefore not surprising that there is an increasing demand for, and expectation of, genetic services.
Many patients seen in endocrinology and diabetes clinics are at risk of having a monogenic basis to their disorder, from rare neuroendocrine tumours such as phaeochromocytomas and paragangliomas, and multiglandular disease, to the more common disorder of primary hyperparathyroidism. Maturity-onset diabetes of the young (MODY) and mitochondrial diabetes are also considerations in those with familial diabetes. The practising endocrinologist therefore needs to carefully consider whether a genetic basis is worth exploring by taking a careful family history in the first instance. Diagnosing a hereditary disorder not only benefits the patient, but also their wider family.
Endocrinologists may be knowledgeable about many of the familial endocrine disorders (after all, they are the ‘bread and butter’ of MRCP exams!). However, most endocrinologists may not be familiar with arranging genetic tests, interpreting the reported variants, the need to arrange cascade family screening, providing advice about recurrence risk and reproductive options. Key questions are:
- Is the test a diagnostic test?
- Is it a predictive test where there is a known familial disorder and a known familial pathogenic variant?
- Are they seeking a predictive test in a child for an adult-onset disorder, for which there are clear guidelines from the British Society for Genetic Medicine (www.bsgm.org.uk)?
- Are they seeking a carrier test for an autosomal recessive disorder or an X-linked disorder?
- Are they familiar with the availability of single genes and multiple gene panels (by disorder or an all-encompassing inherited cancer exome panel)?
- Are they aware of the limitations of NGS tests, such as poor optimisation for the detection of dosage changes (small deletions or duplications), and therefore the need to request additional tests such as multiplex ligation-dependent probe amplification (MLPA) analysis?
- Do they know of the timescale for results (on average, 4 months for NGS panel testing, 2 months for single gene testing, 2–4 weeks for predictive genetic testing, 1–2 weeks for urgent prenatal testing)?
- Are they experienced in obtaining formal written consent (standard forms are available from genetics services) for genetic testing, which covers aspects such as sharing results with the rest of the family and preparing the patient for the possibility of unexpected results? This includes the possibility of finding a variant of uncertain significance (VUS), usually a novel missense variant in a gene where the pathogenic changes are commonly loss-of-function variants. Interpretation of such variants requires expertise and additional training.
Once a genetic diagnosis is confirmed, most affected individuals are naturally concerned and anxious about the risk to their immediate family and seek advice about risk to their relatives, their future children and how to access genetic testing and screening for disorders. Those of reproductive age do not wish to pass on their disorder to their children and therefore seek information about the options available.
A joint clinic with a clinical geneticist appears sensible, in which the expertise of both specialties can be harnessed for optimum patient management. Clinical genetics services in the UK are offered regionally in a ‘hub and spoke’ model. Specialist genetics multidisciplinary clinics are often held in regional tertiary teaching hospitals, which draw patients from the whole region served and often quite a way beyond, depending on the geography covered by the referring specialist service, e.g. head and neck paragangliomas referred by a national skull base surgical service. It is standard practice for a clinical geneticist to draw up a family history covering three to four generations. This can be useful for:
- providing detailed information about affected members
- seeking confirmation of the disorder and obtaining a mutation report if available
- identifying the presence of any consanguinity
- identifying at-risk relatives
- determining the likely inheritance pattern
- ensuring that confidentiality is strictly observed between members of the same extended family, except where specific consent to share information is obtained.
The geneticist can inform the patient about the diagnosis or diagnoses in consideration, their inheritance pattern(s) and therefore the potential risks to their relatives, the implications of having a diagnostic or a predictive genetic test, and the implications for insurance policies of the latter test, and also advise when childhood predictive testing is appropriate.
Various reproductive options can also be discussed for couples where any future children are at high risk. These include:
- non-invasive prenatal diagnosis for paternally inherited autosomal dominant disorders or autosomal recessive disorders where the couple are confirmed carriers, or sexing for X-linked disorders
- invasive prenatal diagnosis by chorionic villus sampling or amniocentesis
- pre-implantation genetic diagnosis for disorders approved by the Human Fertilisation and Embryology Authority (www.hfea.gov.uk).
The genetic test is then arranged after written consent is obtained, where the option of sharing their results with family members is included as an integral part (so that future cascade family testing can take place smoothly without breaking confidentiality). The possibility of unexpected results, including a VUS, is discussed in the consent process, as well as anonymous use of the test results to improve healthcare within the NHS (useful for valuable NHS audit projects). If a genetic disorder is confirmed, then the genetics service is well accustomed to facilitating family cascade testing with the generation of an open ‘To Whom It May Concern’ letter that can be passed to the at-risk family members, thereby assisting with GP referrals for these relatives.
The challenge with genetic tests now mainly lies in interpretation of the results and any variants that are detected. Life would certainly be easier
for all practising clinicians who regularly request genetic tests if we had long-established and detailed databases of both pathogenic variants for known disorders and variants present in the general population presumed to be harmless or of low penetrance. Databases for both do exist (ClinVar, www.ncbi.nlm.nih.gov/clinvar; HGMD, www.hgmd.cf.ac.uk; DECIPHER, https://decipher.sanger.ac.uk; gnomAD, https://gnomad.broadinstitute.org) and can prove helpful in many cases, but more information still needs to be gathered and compiled for this process to be facilitated. The UK has led the world on nationally co-ordinated whole exome and genome sequencing research studies (e.g. DDD study, https://decipher.sanger.ac.uk/ddd, and the 100,000 Genomes Project) through our integrated NHS services, and results from these studies are generating much-needed information for the genomic databases, which will help ease the burden of interpreting variants in the future.
NHS England, through its NHS Genomic Medicine Service initiative (www.england.nhs.uk/genomics/nhs-genomic-med-service), has recently brought about reconfiguration of genetics laboratory service provision through commissioning seven Genomic Central Laboratory Hubs working in conjunction with the clinical genetics services, capitalising and building on the output of the 100,000 Genomes Project. This will allow access to the widest range of genetic tests to date. One of the main aims of this change is to embed genomics into mainstream medicine. Therefore, all NHS specialists will have access to, and are expected to use, genomic testing before the end of the year, on whole genome platforms where all requests are funded centrally, provided that the testing criteria are met. The requests are placed centrally but testing will be directed to the laboratory assigned to perform the relevant test. Therefore, the time has come for the endocrinologist to become genomics savvy, and a close working relationship with their local clinical geneticists becomes more pertinent than ever.
Soo-Mi Park, Consultant in Medical Genetics, Addenbrooke’s Treatment Centre, Cambridge University Hospitals NHS Foundation Trust