Response to Iliff et al.

Main Text

We thank Iliff et al. for their interest in our work, and we are pleased to reply. We reported that a mutation in MIR184 (MIM 613146) causes autosomal-dominant keratoconus with early-onset anterior polar cataracts (KTCNCT [MIM 614303]) in a large Irish family.¹ The corresponding authors described a US family with a similar ocular phenotype of endothelial dystrophy, iris hypoplasia, congenital cataracts, and stromal thinning (EDICT syndrome), a phenotype which they have since found to be caused by the same mutation.² We do not know whether the mutations have arisen independently or whether the families are distantly related.

There are two notable differences between the phenotypes reported for the affected cases within the EDICT and KTCNCT families. First, four of ten affected people in the EDICT pedigree show iris abnormalities (ectropion pupillae; small, eccentric pupils; or “iris defects”). Mutation of MIR184 is a highly plausible cause of iris abnormalities. MiR-184 upregulates PAX6,³ a deficiency of which causes abnormalities of the iris.⁴ However, iris abnormalities have not been observed in the KTCNCT family members who underwent slit-lamp examination. Second, a distinction has been made between the corneal phenotypes in the two families. Stromal thinning and steepening of the cornea are observed in both families; however, the KTCNCT individuals (unlike those with EDICT syndrome) have ectatic corneas. The diagnosis of keratoconus was based on at least one clinical sign of keratoconus and a confirmatory videokeratographic map. Slit-lamp biomicroscopy revealed key features of keratoconus, including stromal corneal thinning, Vogt striae, and Fleischer rings in affected individuals. The oil-droplet sign and scissoring of the red reflex were observed during a cycloplegic retinoscopy. Videokeratographic evaluation that was performed on each eye with the Topographic Modeling System-1 (Computed Anatomy, New York, USA) was indicative of keratoconus. Unfortunately, no tissue samples are available for histological examination.

The scope of the next-generation-sequencing experiment carried out by Iliff et al. is unclear; however, they claim to have excluded “any potential coding variant that might modify the phenotype caused by the mutation.” We wonder whether—and by what means—Iliff et al. sequenced the whole exome or exons in their 26 Mb linkage interval. We also wonder how many individuals with each subphenotype were included, with whom they were compared, what statistical power ten cases provided, and by what criteria and methods Iliff et al. excluded all possibly functional polymorphisms. A modifying variant does not need to be rare or novel given that it might not cause disease in the absence of the c.57C>T MIR184 mutation. Neither is there any persuasive reason for one to expect that modifiers for the iris or corneal-ectasia subphenotypes should be confined to the linkage interval. The most useful investigation of genetic modifiers of the corneal-ectasia phenotype would be direct genetic comparison of the two affected families. Most significantly, because this disease is caused by mutation of a noncoding RNA, variation within the untranslated regions of miR-184 target genes, regulatory variants affecting miR-184 expression, and variation of other noncoding RNAs should be considered to be at least as important as coding variants.

Clearly, these families have a very closely related phenotype that arises from the same mutation. We believe that the mechanism of disease in these families offers a fascinating pathophysiological insight, and we welcome the opportunity to confirm the phenotype of the Irish KTCNCT family. We expect that within and between the KTCNCT and EDICT families, there exist genetic and environmental modifiers that account for phenotypic variability. Identifying them will not be a trivial task. We urge Iliff et al. not to be dogmatic about their edict.

Web Resources

The URL for data presented herein is as follows:

• Online Mendelian Inheritance in Man (OMIM), http://www.omim.org