Author Response: Genetic Testing and Clinical Characterization of Patients with Cone–Rod Dystrophy

We appreciate the critical reading of our article ¹ by Drs. Thiadens and Klaver, and we fully agree with their statements that good collaboration among clinicians, molecular geneticists, and epidemiologists is warranted, to establish meaningful genotype–phenotype correlations in patients with retinal dystrophies. 

Drs. Thiadens and Klaver question the gene frequencies provided in our study and point out that the genetic testing was not identical for the entire study group. We would like to comment that our study ¹ was not an epidemiologic study and has not been presented as such. As stated in the study's introduction, the goal was to identify and map homozygous regions in a large cohort of patients with cone–rod dystrophy (CRD). We clearly explained in the Methods and in the Results sections that only part of the patients have been screened for known mutations in ABCA4. Moreover, it is obvious that homozygosity mapping can detect only homozygous mutations. Homozygous mutations are detected in ∼35% of Western European patients with autosomal recessive diseases and consequently we did not expect that homozygosity mapping would allow us to detect mutations in the entire study group, as also mentioned in the introduction of the article. 

Perhaps we should not have presented the percentages of CRD cases that could be attributed to the CRD genes, since not all patients were screened for the complete genes. On the other hand, genetic testing of entire genes in large patient cohorts has always been expensive and laborious, and only limited articles present an accurate overview of percentages of mutations in all genes associated with a specific retinal dystrophy ² or in one specific gene. ³ Our study does indicate, however, that mutations in PROM1, CERKL, and EYS are likely to be infrequent causes of CRD. 

Furthermore, Drs. Thiadens and Klaver mention that the diagnosis of the patients in this cohort may be uncertain. Such uncertainty may be true to some extent, as sometimes the final diagnosis changes over the years with progression of the disease or with the development of systemic features. In a follow-up study of 75 patients with an initial diagnosis of Leber congenital amaurosis, the diagnosis was revised at a later stage to a different disease in 30 patients. ⁴ This actually emphasizes the value of molecular genetic testing to aid a correct diagnosis. Genetic technologies are developing at a tremendous pace, and it is currently possible to screen all retinal dystrophy genes in a patient's DNA in one experiment, by using a resequencing chip ⁵ or next-generation sequencing (NGS). We are arriving in an era in which it may even be faster to perform genetic screening of all retinal dystrophy genes in a patient's DNA, rather than to await the results of clinical tests that, particularly in young children, can be challenging or impossible to perform. Besides aiding the diagnosis, we expect that NGS will bring accurate epidemiologic data of mutation frequencies in the near future.