Invited editorial in regards to phenotypic variant of CLN3 mutation

We are thankful for the opportunity to have presented this case for peer review,¹ the vital and important criticism obtained after it was published, the swift response by the editorial staff of the AJOCR, the opportunity to clarify the intention of the report and address its issues, and lastly, offer additional considerations for the use of broad panel genetic testing. In this disputed case, we had the good intention of reporting the retinal findings in an individual which were thought to be a novel phenotype associated with a heterozygous (mono-allelic) pathogenic variant in the CLN3 gene. Given the bilateral retinopathy, insidious nature of the presentation, and the lack of access to family history (patient was adopted), we obtained no-cost large panel genetic testing for inherited retinal degeneration (IRD) genes to determine if genetic etiology was a possibility. In retrospect, after discussion with the readers of AJOCR and ophthalmic genetics clinicians, a mono-allelic variant in CLN3 is unlikely to be disease-causing. Rather, the differential diagnosis of inactive bilateral multifocal choroiditis is the more likely etiology, given the asymmetric nature and “punched-out” character of the chorioretinal lesions. The existing databases of genotype and phenotype IRD variants are not widely known or easily accessible to non-specialists, and the clinical context of the genetic variants require an understanding of the genotype-phenotype correlations that arise from knowledge of these databases and published case series and case reports. While it was not our original intention, this case illustrates the pitfalls of unfettered genetic testing in a retina clinic, which could lead to erroneous attribution of genetic variants to just about any clinical finding without careful consideration. Review of this and similar cases with a qualified genetic counselor and/or an ophthalmic genetics clinician is recommended. Thankfully, the two suppliers of no-cost large panel IRD genetic test also offer no-cost genetic counseling and this was indeed offered to our patient. We hope that this case represents an educational opportunity for retinal specialists that have been using or are contemplating the integration of no-cost large panel genetic testing for IRDs into their clinical practice.

Conflicts of interest

The authors do not have any conflicts of interest related to this study.