The future is in your genes

Phenylketonuria (PKU) is a genetic disorder that causes the build-up of the amino acid phenylalanine in the blood. Although babies born with this disorder initially appear normal and healthy, after a few months the children develop permanent intellectual disability, with delayed development and seizures frequently occurring. PKU is, however, symptomless if infants are given the correct treatment and the child will grow to a normal, healthy adult.

Many serious genetic diseases are initially symptomless but benefit greatly from early intervention. This is why all newborn babies in the UK are given a blood spot screening test; this checks for diseases such as PKU, cystic fibrosis and sick cell disease. These screening programs allow families either some piece of mind or time to prepare for the future of their child who may require specialised care.

The costs of sequencing DNA have, in recent years, dropped remarkably. The newborn blood spot test costs in the region of £65 and to sequence an entire human genome in now a little under £3500. A lot of the human genome however does not code for proteins (faulty proteins being the most likely cause of genetic disorders) – a vast amount of the human, around 99%, regulates the activity of the coding 1%, plays a structural role or has a currently unknown function; it is unlikely to be all completely unnecessary “junk”. The 1% of the genome that does actually encode proteins, the exome, can be sequenced for around £650, with remarkable accuracy.

Would you like to know if you were going to get Alzheimers? ©Tom Varco; Image credit: WikimediaCommons

Whilst this focus on prices may seem cold and calculating, the cost of research plays a major role in diagnoses. A child suffering from a mysterious illness twenty years ago, say a case of inflammatory bowel disease that was causing the gut to leak into the abdomen, may well have undergone years of intensive surgery with no successful outcomes. But now, as in the case of Nicholas Volker, a full sequencing of his genome allowed the cause to be identified as a mutation in theXIAP gene, leading to a leukaemia-like disorder. One bone marrow transplant later and Nicholas is able to lead a healthy life.

Exome sequencing is allowing patients with rare disorders to finally get the diagnosis that they need, both to receive treatment and plan their lives correctly – for example the tragic case of an infant girl with late stage liver disease, that was found to be caused by a series of mutations that would soon lead to fatal neurodegeneration and heart failure, this spared the infant the further trauma of a liver transplant and meant that her family was able to simply keep her comfortable for her last days. Although these diseases are rare, each one affecting maybe a handful of people across the whole world, rare diseases add up. Taken all together, rare hereditary diseases affect 25 million people in the United States alone.

Rare hereditary diseases affect 25 million people in the United States

Sequencing, for these patients, means a diagnosis rather than just treatment of symptoms. Here is it used for an explanation, not as a forecast; but this is what it could be. With sequencing costs reducing every year, it may not be long until all newborns have their entire exomes sequenced at birth, or until you may go to your doctors and ask what your future health may hold for you.

Children of patients suffering from Huntington’s diseaseare already offered a test to see if they carry it themselves; if they are, they may wish to avoid passing it on should they also have children. In the case of Huntington’s, carrying a faulting a faulty HTT guarantees that you will suffer from the neurodegenerative disorder. However few other diseases are quite so clear cut.

When Angelina Jolie found out she had a mutation in her BRCA1 gene, increasing her risk of breast cancer to 65-87% (calculations are dependent on the details of the mutation) she decided to undergo a double mastectomy, reducing her risk to getting breast cancer to <5 able="" again="" an="" and="" being="" do="" future="" genetic="" have="" health.="" here="" impact="" incredibly="" invoke="" knowing="" may="" mutations="" on="" one="" positive="" reduce="" risk="" s="" something="" the="" they="" to="">

But would you like to know if you had a copy of a variant APOE4 gene, doubling the risk of Alzheimer’s disease? Alzheimer’s is currently incurable, and can leads to years of suffering, both to the patients and their families. Many people may feel uncomfortable knowing that such a fate is likely to await them, yet others would argue that this would allow those at high risk to prepare better for their future.

Pre-emptive treatments, from statins given to those with moderately high cholesterol to a half aspirin a day for those at risk to blood clots, have been with us a long time. Perhaps it is time that these measures become tailored to each individual, dependant in their genetic profiles. In countries with private health care however, this is a sticking point. Insurance premiums for those deemed high risk for various diseases would do through the roof, likely preventing health care access to those who actually need it most.

The NHS too, may be unable to support such a system. Lifetime treatments become incredibly expensive, especially for a disease that may or may not have come to pass. Could a “life time risk” cut-off be put in place? How high would your disease risk have to be to quality for the treatment? 40%? 80%?

Currently, however, exome sequencing is only an option for those suffering from rare diseases. The human genome contains so many variants from person to person that evaluating risk for many complicated combinations of mutations will require vast amounts of in-depth knowledge of our genetic code, as the signal-to-noise ratio of mutations is still far too high to be clear. Drugs companies too will need to change their stance. Instead of making universal treatments worth billions of dollars, every drug will have to be targeted for individuals.

Ethical issues come in to play here too. Would you counsel those carrying many risky mutations to avoid having children, and those with particularly health codes to donate sperm and eggs? These are extreme fears, and cries that exome profiling will lead to eugenics have already been made, but likewise could a doctor morally allow two people to have a child if it meant that child would suffer from a debilitating disease.

These barriers, both ethical and financial stand still stand in the way of genetic health profiling for all, and many years of debates are yet to come as we try to navigate out way through the rapidly changing landscaper of modern medicine.

Published on The Yorker Online