The great beyond

    Progress on rare genetic diseases shows the medical value of outliers.

    “Treasure your exceptions! When there are none, the work gets so dull that no one cares to carry it further. Keep them always uncovered and in sight. Exceptions are like the rough brickwork of a growing building which tells that there is more to come and shows where the next construction is to be.” Geneticist William Bateson offered this advice in 1908, around the dawn of modern genetics following the rediscovery of Gregor Mendel's pea plant experiments, and it remains sound today.

    Every empiricist must contend with exceptions to the rule, which can illuminate research in unpredictable ways. Bateson was urging vigilance in observing rare offspring of plants and animals, which may point to new phenomena that can inform us about the broader biological context. The same is true for rare diseases, which often have a genetic basis.

    This being a leap year, the extra day, 29 February, was designated Rare Disease Day. It aims to give a voice to the families of millions of exceptional children who are born each year with a rare or undiagnosed disease. Liddle syndrome and Tangier disease, for example, affect a tiny number of people, especially compared with high blood pressure, diabetes or heart disease. The attention these rare disorders receive from pharmaceutical programmes, the medical community and academic research has historically been correspondingly small, despite the significant disease burden they bring to the health-care systems of many countries.

    Perhaps up to one-fifth of paediatric hospital admissions worldwide are the result of Mendelian disorders — uncommon diseases that follow inheritance patterns outlined by Mendel in the nineteenth century, usually caused by mutations in a single gene. If not deadly, these conditions often demand expensive life-long care.

    Beyond the economic factors are the harrowing stories of parents trying to find treatment or even a diagnosis for a child with an exceptional problem. For rare diseases for which there are perhaps only one or two experts in the world, it typically takes a broad network of parents working together for the families to find help, or even information.

    “Genetic disease has a long history of teaching scientists about normal biological processes.”

    The rapid rise of genome sequencing and its increasing use in paediatric clinics offers some hope. Children with known diseases can be diagnosed faster than before, and those with previously unknown syndromes might be able to get a better understanding of the reason for their illness.

    Rare disorders have conventionally been used to sharpen the tools of genetic medicine. Diseases that affect several families are prime targets for unpicking and understanding the effects of human gene mutations. With the development of better tools, researchers are now equipped to tackle even the rarest disorders. As the price of sequencing drops and analysis tools become more sophisticated, fewer individuals are needed to pin down the common genetic cause.

    As the News Feature on page 20 highlights, one small clinic serving Amish and Mennonite communities in the United States is at the forefront of these efforts. Through sequencing and other tools, the paediatricians there estimate that they can discover 5–15 new disorders per year. They think that about half should be treatable if the underlying cause is identified early.

    The clinic is in an exceptional position, however. The communities it serves come from small founder populations, have a good knowledge of family history and a high rate of intermarriage. All of this makes unravelling the genetics of disease easier than in a more diverse population. But there are two reasons to treasure these exceptions. First, genetic disease has a long history of teaching scientists about normal biological processes, and can sometimes give insight into the processes that go awry in other, more common diseases. Liddle syndrome, for example, is one of several genetic disorders in which high blood pressure is a major defining factor. Tangier disease causes low levels of 'good' cholesterol in the blood, and many of those affected have premature atherosclerosis.

    The second reason relates to a growing appreciation of the heterogeneity of 'common' diseases. Projects that sequence tumour genomes from dozens of patients — who by standard diagnostic measures have the same cancer, and thus the same disease — have revealed that each tumour has unique and divergent genetic properties. Indeed, the real work may begin once we realize that every case is an exception.

    Rights and permissions

    Reprints and Permissions

    About this article

    Cite this article

    The great beyond. Nature 483, 5–6 (2012).

    Download citation


    By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


    Quick links

    Nature Briefing

    Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

    Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing