Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population

Abstract

Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a "telegenetics" approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.

Keywords: Leber congenital amaurosis; achromatopsia; inherited blindness; inherited retinal degenerations; paediatric ophthalmology; panel-based next generation sequencing; retinal dystrophy; retinitis pigmentosa.

Figure 1

Multimodal retinal imaging of 2 paediatric IRD cases. (A,B). Colour fundus photographs (FF450 plus, Carl Zeiss MediTec, Dublin, CA, USA) showing an altered foveal reflex. (C,D). Fundus autofluorescence images showing symmetrical hypoautofluorescence at the fovea with a hyperautofluorescent margin. (E,F). Optical coherence tomography (iVue 80, Optovue Inc., Fremont, CA, USA) showing outer retinal cavitation at the fovea. This 13-year-old female had Stargardt disease due to compound heterozygous pathogenic ABCA4 variants. (G,H). Colour fundus photographs of the right eye showing optic nerve head pallor, arteriolar attenuation, and intraretinal pigment migration. (I,J). Fundus autofluorescence showing a hyperautofluorescent macular ring and peripheral hypoautofluorescence. This 10-year-old female had autosomal dominant RP due to a likely pathogenic PRPF8 variant.

Figure 2

Mean visual acuity against age (in years) for all patients. Blue dots represent the right eye and orange dots represent the left eye.