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Only six other children in the world are known to have the same condition as Lillian Yuska (Image: Children鈥檚 Hospital of Wisconsin)

Genome sequencing is bringing a medical revolution for families with rare diseases, and the rest of us will benefit too. Find out how in this special report

Editorial: 鈥�The right to genetic ignorance鈥�

FOR the Yuska family, the future of medicine is here. Thanks to genome sequencing, parents Danielle and Erik have a name for the mysterious condition that they feared would take the life of , and they have an idea of what her outlook might be.

Born prematurely, Lillian struggled to feed, suffered from chronic vomiting and diarrhoea, and succumbed to repeated infections. After shuttling for years from specialist to specialist, the Yuskas now know that Lillian has , caused by a mutation in , which disrupts both gut function and immunity. Just six other children worldwide are known to have the condition. 鈥淚t鈥檚 real rare, and little is known about it,鈥� says Danielle.

Families afflicted by rare genetic disorders will be the first beneficiaries of genome sequencing. But everyone else will benefit, too, and more than you might imagine. It turns out that conditions any of us may face 鈥� such as heart disease and diabetes 鈥� may also be triggered by similarly rare mutations.

鈥淢ost common diseases are merely a collection of rare diseases that happen to have the same end point,鈥� says , a paediatric geneticist at the Medical College of Wisconsin (MCW) in Milwaukee. In other words, common conditions are actually rare disorders in disguise, which means that the same methods that helped the Yuskas promise to deliver personalised medicine for us all.

To witness this emerging revolution, I visited the pioneering clinic that delivered Lillian鈥檚 diagnosis, run by MCW and the Children鈥檚 Hospital of Wisconsin, and began an exploration of my own DNA that hints what might be possible 鈥� and the challenges ahead.

Over the past three years, the Milwaukee clinic has sequenced the genomes of around 40 patients. This has boosted its rate of diagnosis of rare genetic disorders from around 10 per cent to 27 per cent ().

The clinic got off to a spectacular start with its first patient. At 4 years of age, inflammatory bowel disease was so severe that food in his gut would leak into his abdomen. The Milwaukee team zeroed in on a mutation in , a gene that, when damaged, can cause .

Thumbs up for Nic Volker鈥檚 diagnosis (Image: Gary Porter/The Milwaukee Journal Sentinel)

To avoid that outcome, and suspecting that the defect might also be causing Nic鈥檚 immune system to attack his bowel, his doctors recommended a bone-marrow transplant (). It worked, and while it was too late to save Nic鈥檚 colon, .

Not every diagnosis has led to a similar breakthrough. But for families like the Yuskas, ending the diagnostic roller coaster is in itself a huge step forward. For a bleak couple of weeks, the leading contender for Lillian鈥檚 condition was , which typically kills people in their 20s. 鈥淎fter that, we decided not to research the things she was being tested for,鈥� Danielle says.

Lillian鈥檚 actual diagnosis holds more hope: while her health problems won鈥檛 go away, there鈥檚 no reason to conclude that her life will be cut drastically short. 鈥淣ow we need to find out how best to care for her,鈥� says Danielle.

Even when the news is the worst possible, families have been grateful to know what鈥檚 wrong. Dimmock recalls telling the mother of an infant with severe liver disease that the mutations responsible would quickly lead to fatal neurodegeneration. The mother cried, then turned to Dimmock and said: 鈥淭hank you. That really helps.鈥� The diagnosis meant that her daughter could be spared a liver transplant that would have proved useless.

Although I鈥檓 in good health, I asked the Milwaukee clinic to analyse my 鈥溾��. Essentially, the exome is the part of the genome that is 鈥渞ead鈥� to make proteins. While it accounts for only about 1 per cent of the total DNA (the rest regulates gene activity, or is 鈥渏unk鈥�, without a known function), it is thought to host around 85 per cent of the genetic variants that cause disease. I鈥檇 previously had my genome scanned by companies that use DNA 鈥渃hips鈥� to analyse about 1 million common variants, but an exome contains far more information.

Geneticists had hoped that heritability of common conditions like heart disease would be explained in large part by a few relatively common genetic variants. It hasn鈥檛 turned out that way. Instead, the genetic roots of common disorders seem to be spread across a plethora of rare mutations 鈥� some of which may even be unique to their carriers.

This transforms the process of genetic discovery. To find common disease-causing variants, you might recruit a thousand people with the condition in question, plus a similar number of controls, and look for variants that seem to be inherited with the disease. This is how geneticists know, for instance, that my single copy of the in the gives me 鈥� together with about 1 in 5 people of European ancestry 鈥� about twice the typical risk of developing Alzheimer鈥檚 disease.

But if a thousand people with the same external symptoms have hundreds of different mutations causing them, finding the gene variants responsible becomes a needle-in-a-haystack problem.

鈥淗undreds of different gene mutations could be causing the same external symptoms鈥�

That might sound hopeless, given that a typical genome contains several million departures from the . But you can winnow down the list of candidates using algorithms that predict whether a variant is likely to disrupt a gene鈥檚 function. A premature 鈥渟top鈥� instruction, for instance, which cuts a protein short, is an obvious candidate for further scrutiny.

These algorithms work in various ways. Some flag up mutations if they occur in DNA sequences that differ little from species to species. The thinking goes that if evolution has preserved a gene鈥檚 sequence, then any change in it is likely to be bad.

Other algorithms are more sophisticated, for instance assessing how gene variants might change a protein鈥檚 shape, which might affect how it works.

The Milwaukee clinic鈥檚 bioinformatics team, headed by Liz Worthey, runs five of these algorithms. To get a sense of what they do, I ran three on my exome, producing a list of almost 1700 potentially damaging variants. That might sound worrying, but it鈥檚 actually normal. 鈥淗ealthy people tend to have healthy genomes,鈥� I was reassured by , a clinical geneticist on the Milwaukee team, who talked me through the results in the presence of a genetic counsellor.

A mutation may be damaging to a protein without causing disease. This is because many of our metabolic pathways have a degree of redundancy, which means that when individual proteins 鈥渂reak鈥�, there are often others available to take the strain.

What鈥檚 more, some of the variants highlighted by the prediction algorithms will be sequencing errors. Quality control 鈥減roof-reading鈥� of the sequence is good at spotting obvious errors. However, genome sequencing technologies, while rapid and cheap, currently lack the accuracy of the old-school method known as Sanger sequencing. This is why the Milwaukee team confirms every variant it suspects of causing disease using the Sanger method.

While sequencing methods and the tools used to sift for damaging mutations have advanced far enough to spot single variants causing rare diseases, the signal-to-noise problem becomes more challenging when the symptoms are common. And as I can vouch, it鈥檚 possible to spend days exploring 鈥� variants which look as if they might be damaging, but which are probably of little significance. As our knowledge of rare variants expands, though, and prediction algorithms become more sophisticated, the genome鈥檚 dark matter should come into view.

Even at this early stage, there are valuable nuggets to be mined from a typical genome 鈥� as I found (see 鈥�What I found in my DNA鈥�). The most useful information surrounds carrier status for genetic disorders and clues about how commonly used drugs are likely to work.

The full benefits of the genomic revolution will come when doctors are routinely able to pick out the rare variants triggering certain symptoms, and prescribe drugs that have been specifically designed to correct the biochemical pathways concerned.

This may take several decades. Not only must geneticists get better at deciphering the significance of specific variants; drug companies will also need to shift their focus from developing blockbuster drugs sold to millions to supplying the niche markets of personalised medicine.

Thanks to the trail blazed by the Milwaukee clinic and a handful of others, that journey has begun. As , who heads MCW鈥檚 Human and Molecular Genetics Center, told me: 鈥淵our genome is going to get more and more meaningful.鈥�

This article appeared in print under the headline 鈥淥ur genomic future鈥�