Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33


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Introduction

However, there is also evidence that many people have a strong desire to receive a broad range of results from genetic testing, including uncertain results, and are uncomfortable with the idea that decisions about non-disclosure might be made without involving them [ 29 ].

The fear is that disclosure of uncertain variants will lead to over-diagnosis and over-management, with variants inappropriately being treated as if pathogenic. This nominally shifts the responsibility to the next person in the chain but feels unsatisfactory for all concerned. Another issue arising from improved sensitivity is the ability to find genetic variants that are unrelated to the clinical problem that a patient presents with, but that may be relevant for their health in other ways.

This may be viewed as positive or negative, but working out how to handle this information raises difficult questions. However, these recommendations proved controversial. The main debate at the time centred around whether patients should have a right to choose not to know such information [ 31 ]. However, what this might mean on an individual basis is often unclear. Most of our knowledge regarding the effects of variation in any given gene has been gathered by observing people who have been identified as having variants in the gene because they were tested as they had a personal history or family history of disease, biasing the sample from which our conclusions are drawn.

It is less clear what it might mean to find, for example, an apparently pathogenic variant in a gene linked to cardiomyopathy in a person with no personal or family history of heart problems. To what extent should testing and subsequent screening be offered in a family based on an incidental finding of a genetic variant thought to be predictive of a particular condition, if there is no clinical evidence that anyone in the family, including the person in whom the genetic variant in question was first identified, is actually affected by it?

Broad genomic testing also has the potential to detect carrier status for recessive and X-linked conditions. From population studies, we know that being a carrier for a genetic condition is very common. For most people, being a carrier will have no impact on their life at all. However, if their partner happens to be a carrier for the same condition then the implications could be very profound, as each of their children would have a one in four chance of being affected by the genetic condition.

This is particularly relevant for couples who are known to be biologically related [ 34 ], and couples with common ancestry, as they will have a higher chance of both being carriers for the same recessive condition. Carrier screening for various autosomal recessive diseases has been available in some instances for many years, for example screening for carrier status for Tay—Sachs disease for people of Ashkenazi Jewish ancestry has been offered since the s [ 35 , 36 ].

More recently, advances in technology have led to development of expanded carrier screening tests, which check carrier status for multiple diseases simultaneously and are often less targeted towards particular genetic populations [ 37 ].

Introduction

The increased scope of carrier screening, combined with the recognition that it is very common to be a carrier for one or more recessive genetic conditions, has led to an increasing move to consider carrier results for recessive genetic conditions on a couple basis, where carrier status is only communicated if it would be relevant in the context of a particular relationship i. Objections to this approach are that by not communicating individual carrier results, a person would not know this information for future relationships, and their family could not access cascade screening to see whether they are also carriers.

However, these objections could be obviated by widespread adoption of couple carrier testing — a person or their close relatives could find out their carrier status if relevant when they next had a couple carrier test in the context of their new relationship. In some ways, this could be seen as comparable with management of infectious disease — lots of healthy people carry MRSA, but very few die of MRSA infection. People are therefore screened at times when they might be especially vulnerable to becoming unwell from MRSA, or when they might pass it on to others at risk, for example when admitted to hospital, rather than being tested at random points when they are generally well.

For many years, clinical genetics input has at times influenced acute care, for example in diagnosing trisomies in the neonatal period, or informing the care of babies born with ambiguous genitalia. However in many circumstances, the key contribution of clinical genetics was in providing a post hoc explanation for serious medical problems, rather than in influencing treatment decisions on a real-time basis.

Recent developments in genetic/genomic medicine

This is changing as the availability of exome and genome sequencing increases, as shown by Case Study 3. A recent study in a neonatal intensive care unit in Texas studied outcomes for infants who were referred for clinical exome sequencing, and found that A young woman was referred for exome testing having spent months in a coma. From childhood she had experienced sensory problems, and as a young adult she had gone on to develop seizures which deteriorated into status epilepticus, necessitating ventilation on intensive care.

After 3 years during which all other avenues had been explored, analysis of her exome was proposed. An unexpected diagnosis of pyridoxine-dependent epilepsy was found; this had not previously been considered as classically it causes seizures in the first few months of life.

Background

She began treatment with pyridoxine vitamin B 6. From that point on she had no further seizures and her clinical situation transformed.


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Over a 6-month period she was weaned off all of her anti-epileptic drugs, and was able to return to a normal life. As well as guiding treatment choice, genetic testing will increasingly influence what doses are prescribed, and whether medications are considered unsuitable in view of a high risk of an adverse reaction. Around the time that the Human Genome Project was completed, there was considerable excitement about the possibility of genetic testing guiding use of medication in the clinic [ 44 , 45 ].

The potential of genotype-driven drug dosing has for the most part yet to be realised, in part because the interaction of the genetic factors involved is sometimes complex, and in part because environmental factors may also have a significant impact on how a person responds to a drug.

Developments in molecular diagnostics

For example, genotype-driven prescription of warfarin, which has notoriously wide inter-individual variation in dosage requirements, largely remains in the realm of research [ 46 ]. However, for some drugs, pharmacogenomics has already had a significant impact in reducing morbidity and mortality. Similar screening is likely to become more widespread as we learn more about genetic risk factors for adverse drug reactions. For example, there are increasing suggestions that the mitochondrial variant m.

Genetic testing is also being used more extensively in the prenatal setting, in part because of developments in non-invasive prenatal testing and diagnosis, which allow genetic screening or testing of a developing pregnancy by doing a blood test for the mother [ 52 ]. This removes the risk of miscarriage associated with conventional prenatal tests chorionic villus sampling or amniocentesis. While this is in some ways a stride forward, it raises various ethical issues, as the technical test safety may lead to such testing becoming viewed as routine. This raises the concern that couples will give less careful consideration as to whether they really want to know the results before having such tests, and that women may feel that there is an expectation that they should have testing.

The worry is that this could potentially lead to people feeling under pressure to terminate pregnancies in response to genetic test results including in situations where the clinical implications of the results may be far from clear [ 53 ]. The expanding options for genetic testing and the escalating expectation for quick results to drive clinical management mean that testing provision is increasingly being pushed out of highly specialised genetics centres into mainstream medicine.

For example, many women with ovarian cancer will now be offered BRCA testing via their oncology team, and only referred to genetics if needed based on the test results [ 54 ]. Genetics appointments now frequently focus on interpretation of tests already done, working out if the test outcome seems to match the clinical problem, and arranging testing and surveillance for family members. As clinical services have increasingly grown to expect and demand genetic answers for patients with complex health problems, on a broader societal level the hunger for genetic information also seems to be increasing.

Direct-to-consumer tests currently sit outside much of the regulation that governs clinical genetic testing, but claim to provide insight into issues as diverse as ancestry, nutrition, athletic ability, and child talent [ 56 ]. Many testing providers also claim to help provide insight on health, though the information provided by many direct-to-consumer companies is far from comprehensive.

For example, a recent analysis of 15 direct-to-consumer genetic testing companies advertising to U. Human Genetics Commission principles for good practice regarding consumer information [ 57 ].


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However, clearly many people see a value in receiving genetic information and are prepared to pay for this. This marks a shift from genetic testing in order to explain health problems or for people at high risk of developing specific genetic conditions, to testing of healthy people with the rationale of facilitating life planning. This idea has been taken to the extreme with initiatives such as the BabySeq project, exploring the medical, behavioural and economic impacts of integrating genome sequencing into the care of healthy newborns [ 61 ].

A healthy medical student was given a direct-to-consumer genetic test for Christmas, and explored the raw data from this test using an online interpretation programme, finding a variant in MYBPC3 that was predicted to cause hypertrophic cardiomyopathy. He was understandably worried by this result, taking time off university as he came to terms with it, and giving up running, which he used to really enjoy. He was seen in a hypertrophic cardiomyopathy clinic and had an expert cardiology assessment including ECG, echocardiogram and review of his family history.

He was found to have no clinical evidence of hypertrophic cardiomyopathy, and further genetic testing showed that he did not actually have the disease-causing MYBPC3 variant that the online interpretation programme had identified.


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However, he continued to feel anxious about his risk of heart problems and decided to give up running permanently. Information provided from direct-to-consumer testing may be unreliable, especially where online interpretation programmes are used to further explore the raw data from the test: the level of quality control may be very different from that of accredited genetic laboratories, increasing the likelihood of false positives, false negatives and sample mix-up.

Many direct-to-consumer genetic tests involve no meaningful pre-test counselling — people are often totally unprepared for the information that might come out of such testing and are unaware that it might be wrong. The familial nature of genetic information has always generated discussion as to how to respect the confidentiality of individual patients while ensuring that their close relatives have access to information that may be relevant for their own health and life choices.

Clinical guidance in this area has increasingly taken the stance that genetic information should be confidential to families, not individuals though the personal consequences of having a genetic change for a given individual should be confidential to them alone [ 62 ]. The consequences of this shift are still being navigated in the clinical setting — research indicates that patients often see genetic information as belonging to their family rather than exclusively to them [ 63 ], but healthcare professionals are often reticent about taking a familial approach to the confidentiality of genetic information in practice, worrying that this stance could disrupt family dynamics or erode patient trust in the health service [ 64 ].

One of the most exciting recent developments in genetics and genomics is the prospect of treatment for an increasing number of genetic conditions. However this topic has to be treated with caution as the practical reality for many patients and families is that though promising research is ongoing, meaningful treatment is not possible in many cases. Even in situations where evidence-based treatments have been developed, the expense of many of these therapies risks making them inaccessible. Many different approaches have been taken to try to treat genetic conditions.

Gene therapy, which involves delivering functional genetic code, is one approach but its success has been widely variable, often due to difficulty in developing vectors that can deliver genetic material into affected tissues at sufficiently high levels without being destroyed by the immune system. In certain situations this approach can be highly effective, for example promising results have been achieved in various eye conditions, likely because eyes are small and easily accessible, and have a privileged relationship with the immune system [ 67 ].

Pathology and Laboratory Medicine Service

In cases aiming to deliver gene therapy to a wider area, such as the lungs or the muscles, treatment attempts have generally proved more challenging [ 68 , 69 ]. Other approaches include use of small molecules to modify various steps in the pathway from gene to functional product.

For example, Eteplirsen aims to treat Duchenne muscular dystrophy in certain patients by influencing splicing machinery to skip exon 51 from mature DMD mRNA, restoring a more functional reading frame so that a shortened version of dystrophin can be successfully translated [ 70 ]. Ivacaftor potentiates the action of CFTR channels in some patients with cystic fibrosis GD pathogenic variant [ 71 ].

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Enzyme replacement therapy is being trialled to treat children with mucopolysaccharidoses, for example idursulphase infusions in mucopolysaccharidosis type 2 [ 72 ]. While lots of these therapies are very exciting and show demonstrable changes at the molecular level in clinical trials, these cellular changes do not always clearly translate into improvements in clinically relevant outcomes. The therapies are also often hugely expensive, which raises very difficult ethical questions regarding whether limited resources should be spent on such treatments where there is often only limited proof of clinical efficacy.

However the increasing possibility of future treatments for genetic conditions is influencing clinical decisions around the care of very ill children.

Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33 Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33
Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33 Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33
Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33 Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33
Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33 Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33
Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33 Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33

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