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Education And Debate

Ethical review of research into rare genetic disorders

BMJ 2004; 329 doi: (Published 29 July 2004) Cite this as: BMJ 2004;329:288
  1. M Parker, reader in medical ethics (,
  2. R Ashcroft, Leverhulme senior lecturer in medical ethics3,
  3. A O M Wilkie, Nuffield professor of pathology2,
  4. A Kent, director4
  1. 1 Ethox Centre, Department of Public Health, University of Oxford, Oxford OX3 7LF
  2. 2 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS
  3. 3 Medical Ethics Unit, Imperial College London, London W6 8RP
  4. 4 Genetic Interest Group, London N1 3QP
  1. Correspondence to: M Parker
  • Accepted 13 July 2004

Although some work on rare diseases is clearly clinical investigation and some clearly research, much activity falls uneasily between the two. Where should we draw the line and how can we ensure research gets appropriate ethical review?


Consider this case. A clinical geneticist telephoned a medically qualified researcher to discuss a patient with an unusual combination of clinical features. The patient presented a puzzle for diagnosis and for counselling about the genetic risk. Two months later, the clinician sent the researcher DNA from the patient, together with clinical photographs and copies of clinical letters. No mutation hotspots were found in relevant genes, and the sample was added to a “research panel.” The clinician made further contact two years later, asking whether there were any positive results (the reply was negative) and providing some further clinical information.

Eventually, a further year and a half later and after tests of 13 genes had given negative results, the researcher contacted the clinician to say that a potentially pathogenic change in the DNA had been identified. The clinician was asked to obtain samples from the unaffected parents. The mutation was not present in either parent, establishing that the change had arisen de novo in the patient and was the cause of the clinical problem. Hence, three and a half years after the initial contact, the researcher had established unequivocally the correct diagnosis, mechanism of inheritance, and appropriate molecular test for the patient's condition.

Should this be considered research or clinical investigation?

Problems of research classification

Treating such cases as research creates important problems because of the process of ethical review. The first problem is that research ethics committees require consent to be closed—that is, samples must be used for a specific purpose and time which are clearly defined in advance. Small sample sizes in research into rare diseases …

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