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A Clinician's Plea news & views because it seems to be genetically indis- comparing both gene transcripts in the to a target for therapy. Thus, the genetic tinguishable from other variants embed- same sample, both methods decrease the community continues to require more tools ded in this haplotype block. The advent of effects of environmental and other con- to efficiently pinpoint risk variants that whole-genome association studies using founding factors. They also have advan- affect gene expression. There is no doubt the haplotype map11 will probably impli- tages over in vitro techniques, such as that many more inventive approaches will cate a substantial number of new disease transient transfection assays with allele- be developed for this. Ultimately, the associations with indirect markers that specific promoter constructs, as these stud- manipulation of regulatory mutations that are in linkage disequilibrium with rSNPs. ies are executed outside of their normal affect expression levels should be easier chromosome environment. than repairing or modulating the effects of Associations in search of a cause The haploChIP assay is useful as a surro- an abnormal protein. Providing that Pol II (or another DNA- gate marker of allelic variation in gene tran- 1. Cargill, M. et al. Nat. Genet. 22, 231–238 (1999). binding protein with similar properties) is scription, although it does not directly 2. Sachidanandam, R et al. Nature 409, 928–933 (2001). equally useful for testing any human gene, identify the cis-acting polymorphism or 3. Brem, R.B., Yvert, G., Clinton, R. & Krugylak, L. haploChIP has the potential to allow the mechanism that is responsible for this vari- Science 296, 752–755 (2002). testing of each gene contained in a risk ation. This is not surprising, as there are 4. Cheung, V. et al. Nat. Genet. 33, 422–425 (2003). 5. Wasserman, W.W., Palumbo, M., Thompson, W., haplotype block for differential transcrip- many SNPs on the haplotype associated Fickett, J.W. & Lawrence, C.E. Nat. Genet. 26, tional activity. HaploChIP requires that with higher LTA transcriptional activity. 225–228 (2000). 6. Rockman, M.V. & Wray, G. Mol. Biol. Evol. 19, suitable cells or tissues that express the gene The task is also difficult because of the 1991–2004 (2002). are available and that the regulatory variant extensive distances at which transcriptional 7. Knight, J.C., Keating, B.J., Rockett, K.A. & 14 Kwiatkowski, D.P. Nat. Genet. 33, 469–475 (2003) affecting the test gene is heterozygous. control elements can be found . Should 8. Ozaki, K. et al. Nat. Genet. 32, 650–654 (2002). Another surrogate approach to in vivo human geneticists care about finding the 9. Daly, M.J., Rioux, J.D., Schaffner, S.F., Hudson, T.J. & Lander, E.S. Nat. Genet. 29, 229–232 (2001). transcriptional activity is allele-specific true regulatory SNP when the risk gene is 10. Rioux, J.D. et al. Nat. Genet. 29, 223–228 (2001). RT–PCR12,13. This is probably easier to identified and there already are many highly 11. Gabriel, S.B. et al. Science 296, 2225–2229 (2002) 12. Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. & carry out but has an extra requirement that correlated SNPs that tag the disease haplo- Kinzler, K.W. Science 297, 1143 (2002). http://www.nature.com/naturegenetics the RT–PCR product contain polymor- type? Yes! The full knowledge of the risk 13. Cowles, C.R., Hirschhorn, J.N., Altshuler, D. & Lander, E.S. Nat. Genet. 32, 432–437 (2002). phisms, which is not possible for genes variant is important, as it helps refine the 14. Hardison, R.C., Oeltjen, J. & Miller, W. Genome Res. (such as TNF) that lack exonic SNPs. By knowledge of gene transcription and points 7, 959–966 (1997). A clinician’s plea Judith G. Hall © Group 2003 Nature Publishing Department of Pediatrics and Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3V4, Canada. e-mail: [email protected] For the detection of human gene mutations to have practical application, clear clinical descriptions of the affected individuals (as well as those clinically affected in whom mutations are not found) should be part of the publication. Over the last ten years, there has been an in part by the promise that insights into on page 459, or what additional features exponential increase in the number of human health and disease would result. might have been present in the 31 individu- papers describing mutations in genes The large number of excellent articles als with anophthalmia who had no muta- responsible for human disease. Clinicians describing genes mutated in human dis- tions in SOX2, as outlined by Judy Fantes are thrilled that this new information may eases in this issue of Nature Genetics1–8 and colleagues3 on page 461. Did they have translate into meaningful changes in reflects the fruits (and hard work) that are other structural or functional abnormali- health care for affected individuals. We to be celebrated. At the same time, how- ties? What was different about the pregnan- carefully read such papers for clinical ever, they show how little we know about cies of those individuals? Has unusual details to help determine which individu- these genes, how much more work there is behavior developed as they age? Was their als and which families might benefit from to be done and how urgently accurate and mother’s health or nutrition unusual before molecular evaluation or testing. Some- clear clinical descriptions are needed. conception or during the pregnancy? times these details are there, but more Often we read that the ‘found’ gene is often they are not. Thus, clinical geneti- The clinical approach actually one that was previously unknown. cists are frustrated by an inability to deter- A clinician can’t help but wonder what was The gene structure may allow speculation mine to which condition or conditions the different about the 11 individuals with about function, and there may be related reported gene mutation actually refers. Ondine’s curse (congenital central genes that suggest clues as to pathway or The project to sequence the human hypoventilation syndrome) in whom no pathogenesis, but the actual pathogenic genome, nearing completion this year, has mutation in PHOX2B was found, as mechanism must be determined through been a remarkable effort. It was powered described by Jeanne Amiel and colleagues1 the hard work of defining time-specific, tis- 440 nature genetics • volume 33 • april 2003 news & views sue-specific and species-specific expression because the clinician is dealing with details.” Without clear clinical descriptions, and through building animal models of dis- human beings, there are many constraints however, the relevance for human disease, ease. The isoforms, protein folding, control and diagnosis and therapy are the goals. diagnosis and therapy may be lost—and, mechanisms and position along a biochem- The clinician needs clinical details and after all, that is part of the purpose of such ical pathway await elucidation. clues from the affected individual, the fam- work. The clinician usually has a system- Important clues will probably come from ily and a literature review to determine atized way of collecting information (see full clinical descriptions of which tissues are which tests are appropriate to make a diag- box) and storing it for future reference involved, when the onset of disease occurs nosis. Gender, ethnic background, age and (medical records). Some papers that report and what complications develop over time. natural history help in that process. For mutations in a human gene include tables Recognizing the signs and symptoms that example, for individuals with small heads giving phenotypic features2,3,7,8. But too identify exceptions should give hints about (microcephaly), when should Seckel syn- few papers include the clinical features of alternative pathways. For instance, as indi- drome (see the paper by Mark O’Driscoll those individuals in whom no mutation cated by Catherine Dodé and colleagues2 on and colleagues5 on page 497) be consid- was found. But what is or was different page 463, among the individuals with Kall- ered? Historically, individuals with Seckel about those individuals? Occasionally, mann syndrome who have mutations in syndrome have been described as having DNA samples are obtained from cell reposi- FGFR1 (but not among those with other intrauterine growth retardation (small at tories that are notorious for lacking good, mutations), marked craniofacial structural birth for their gestational age) and a head verifiable clinical information—yet another anomalies are often seen. Those individuals size that is much smaller than would be problem! As genomic research moves with Smith–Magenis syndrome who have expected. There are many conditions that towards proteomics, and proteomics moves heart and renal defects are likely to have share these two features9. Thus, the descrip- towards ‘proteotype–phenotype’ correla- chromosomal deletions that include RAII, tion of additional clinical features, such as tions, clarity concerning the clinical features which is described by Rebecca Slager and beaked nose, large-appearing eyes and will become even more important. colleagues8 on page 466. sociable personality, may help the clinician Unfortunately, clinical descriptions are Traditionally, clinicians approach their to determine who should be tested for rarely static. Just as the individual changes http://www.nature.com/naturegenetics work quite differently from basic scien- mutations in ATR, which O’Driscoll et al.5 with age, so do the clinical features. The tists. Medical school provides them with a have found to be associated with Seckel syn- study of the natural history of a genetic dis- broad background in anatomy, cell biol- drome. These ‘newfangled’ DNA-based order is reflected against the normal matu- ogy, physiology, pathology and therapeu- tests are expensive (if you can even get them rational processes (physiologic changes that tics.
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