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  Cheryl Y Gregory-Evans
  Published on: 27 April 2016
• Caveats About Coloboma
  Brian P Brooks
  Published on: 27 April 2016

• Published on: 27 April 2016

  Authors' reply

  • Cheryl Y Gregory-Evans, Senior Lecturer
  • Other Contributors:
    • Matthew Williams, Stephanie Halford, and Kevin Gregory-Evans

  Dear Editors,

  We would like to thank Dr. Brooks and his colleagues for their interest in our article and their valuable remarks. As for the specific issues raised:

  We feel that this as a good time to redefine the use of terms associated with 'coloboma'. We would however suggest that this single word be used to encompass all entities rather than 'uveal coloboma' for two reasons. Firstly, 'uveal coloboma' is...

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  Dear Editors,

  We would like to thank Dr. Brooks and his colleagues for their interest in our article and their valuable remarks. As for the specific issues raised:

  We feel that this as a good time to redefine the use of terms associated with 'coloboma'. We would however suggest that this single word be used to encompass all entities rather than 'uveal coloboma' for two reasons. Firstly, 'uveal coloboma' is too specific and disregards the fact that non-uveal tissue is often the most important tissue affected - especially the retina. Secondly, it implies that the uvea has a central role in aetiology which has yet to be determined. As alluded to in Dr. Brooks' letter, we agree that more specific terms such as 'bilateral uveal and retinal coloboma' could then be used to describe specific patients. As to isolated optic nerve coloboma, whether the entity actually exists or not or is due to other aetiological processes, awaits to be determined and so we think the term should continue to be used.

  We agree with Dr. Brooks' description of the mechanisms that may be involved in closure of the optic fissure. We would however point out that the genes involved do not always act in a positive way to 'mediate closure' or 'set the stage'. For example, there are ocular coloboma genes which are negative regulators of transcription, e.g. ZFHX1B (also known as SIP1) which implies that some genes need to be switched off for closure to occur [1,2].

  Molecular diagnostics will be an important advance in this field. Whilst it is true that, for ocular coloboma, we are not in a good position yet to offer a cost-effective service, this may not be too far away. With mounting experience of single nucleotide polymorphism (SNP) chips in research laboratories for example (costing in the region of £300/$450 per DNA sample), it is likely that these will reach clinical diagnostic laboratory in the near future. As well as mutation screens in specific coloboma genes, we foresee that 'gene-chips' specific for transcription factor SNPs could be used to improve the effectiveness of screening. We look forward to this development.

  References

  1. Gregory-Evans CY, Vieira H, Dalton R, et al. Ocular coloboma and high myopia with Hirschsprung disease associated with a novel ZFHX1B missense mutation and trisomy 21. Am J Med Genet 2004;131A:86-90.

  2. Verschueren K, Remacle JE, Collart C, et al. SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5′-CACCT sequences in candidate target genes. J Biol Chem 274:20489–20498.

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  Conflict of Interest:
  None declared.

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• Published on: 27 April 2016

  Caveats About Coloboma

  • Brian P Brooks, Staff clinician
  • Other Contributors:
    • National Institutes of Health

  Dear Editors

  We very much enjoyed reading the review article by Gregory-Evans et al. on coloboma in the December issue of the Journal of Medical Genetics. The authors should be commended on the most thorough treatment of the subject in the clinical genetics literature to date. In reading it, however, we thought there were a few additional points that required clarification.

  The first is the use of t...

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  Dear Editors

  We very much enjoyed reading the review article by Gregory-Evans et al. on coloboma in the December issue of the Journal of Medical Genetics. The authors should be commended on the most thorough treatment of the subject in the clinical genetics literature to date. In reading it, however, we thought there were a few additional points that required clarification.

  The first is the use of the word “coloboma.” As the authors point out, this term has been used somewhat imprecisely in the past. We would propose the term “uveal coloboma” be used for those ocular malformations that appear to be due to faulty optic fissure closure—including what is listed as iris coloboma, chorioretinal coloboma, and some of the disorders listed as “optic nerve colobomas.” The lattermost term is particularly troublesome to use as it alternatively may mean a uveal coloboma that extends posteriorly to the optic nerve or some other form of anomalous nerve (e.g., the anomalous nerve in papillo-renal syndrome (PAX2 mutations) or the morning glory disc anomaly.[1]) They correctly point out that these latter anomalies may have a different genetic and embryologic basis. To avoid confusion, it might be appropriate to speak of these conditions as “uveal coloboma with optic nerve involvement” and “congenital optic nerve anomlies.”

  Our second comment concerns the mechanism of uveal coloboma formation. The authors do an excellent job at discussing the genes involved in ocular development that may cause uveal coloboma. However, it should be born in mind that non-closure of the optic fissure is the “default state” of the developing optic cup and that failure to close could result from either direct or indirect causes. The former are those specific genes that mediate closure of the fissure; the latter are those genes necessary to “set the stage” for fissure closure. An example of such a gene is MITF, which, when mutated in mouse can produce an optic cup with retarded growth such that the two edges of the optic fissure are not in the right place at the right time to join.[2] An even more indirect mechanism might result from toxicity from environmental agents.

  Lastly, we want to underline the point made at the end of the paper that we do not have good candidate genes to test on a wholesale basis for a patient that presents with coloboma. We believe that it is premature to offer testing for PAX6, CHX10 or SHH, for instance, on all patients, as the yield would likely be very low and results might be difficult to interpret.

  Congratulations again on an overall superb article.

  References

  1. Sanyanusin P, Schimmenti LA, McNoe LA, et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet 1995;9:358-64.

  2. Hero I, Farjah M, Scholtz CL. The prenatal development of the optic fissure in colobomatous microphthalmia. Invest Ophthalmol Vis Sci 1991;32:2622-35.

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  Conflict of Interest:
  None declared.

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