Retinal Phenotype of Patients With Isolated Retinal Degeneration Due toCLN3Pathogenic Variants in a French Retinitis Pigmentosa Cohort

Abstract

IMPORTANCEBiallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. OBJECTIVE To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.MAIN OUTCOME AND MEASURES Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis. RESULTSOf 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.CONCLUSIONS AND RELEVANCE These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.

Hereditary Systemic Diseases Can Have a Predominant Ocular Phenotype, but They Are Still Systemic Diseases

“…Also, the authors did not compare retinal findings among siblings in the 4 sibships in this report. 1 If the clinical course of the disease is consistent within pedigrees, this will give even more credence to their demonstration that the CLN3 pathogenic variants in these 2 groups of patients are associated with phenotypes that are milder than those of patients with classic juvenile NCL. Patients with classic juvenile NCL or Batten disease present with rapidly progressive loss of visual acuity followed by neurological deterioration in the first decade of life and demise as young adults.…”

“…6 Five of the 7 patients were reported to have mild neurological symptoms. While these authors provide more neurological details about their patients than Smirnov et al, 1 workup by neurologists who are experts in NCL and imaging studies with emphasis on more recently recognized changes attributable to CLN5 were not performed. 7 When a gene is expressed exclusively in the retina, its sequence variations will lead to isolated retinal disease.…”

Democratization of genetic screening for inherited retinal degenerations: Historical context and new challenges

“… 1 The CLN3 gene is another good example wherein distinct biallelic variants can either cause a devastating and lethal condition, juvenile neuronal ceroid lipofuscinosis (Batten disease), or an isolated (non-syndromic) retinal degeneration (Smirnov et al, 2021; Mizobuchi et al, 2020; Chen et al, 2019; Ku et al, 2017). 2 , 3 , 4 , 5 …”

Editorial: The genetics of inherited retinal diseases in understudied ethnic groups: Novel associations, challenges, and perspectives

“…Other non-syndromic forms include cone-rod dystrophies (OMIM 120970), Stargardt disease (OMIM 248200), X-linked retinoschisis (OMIM 312700) and many others. On the other hand, the most common syndromic form is Usher syndrome (USH) (OMIM 276900), a combination of hearing loss and RP (Castiglione and Moller, 2022).Although several genetic studies have identified novel IRDs-associated genes and genetic variations, most of these associations and gene prevalence data were based on cohorts in Western Europe and North America (Smirnov et al, 2021;Colombo et al, 2021). Although the genetic basis of IRDs varies among patient cohorts, even replication for the major findings is still lacking in understudied ethnicities (Jaffal et al, 2021).…”

“…Although several genetic studies have identified novel IRDs-associated genes and genetic variations, most of these associations and gene prevalence data were based on cohorts in Western Europe and North America ( Smirnov et al, 2021 ; Colombo et al, 2021 ). Although the genetic basis of IRDs varies among patient cohorts, even replication for the major findings is still lacking in understudied ethnicities ( Jaffal et al, 2021 ).…”