Sten Andréasson

In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were ABCA4 (16.5%), RPGR (6%), CEP290 (6%), and RS1 (5.5%). Other prevalent genes were CACNA1F (3%), PROM1 (3%), CHM (3%), and NYX (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies.

Whole exome sequence analysis was performed in a Swedish mother–father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders.

To investigate whether preoperative retinal function measured by full-field ERG and multifocal ERG is correlated to postoperative visual acuity after macular hole surgery. Standard pars plana vitrectomy with removal of the internal limiting membrane (ILM) was performed on 19 consecutive patients undergoing macular hole surgery. Intraocular gas tamponade with a C₂F₆ gas–air mixture was employed, followed by a face-down position for at least 5 days. The patients were examined with the ETDRS chart, full-field ERG (Espion), multifocal ERG (Veris 6), and optical coherence tomography (OCT) preoperatively, and 6 weeks, 6 months, and 18 months after surgery. The cone 30-Hz flicker implicit time in the full-field ERG reflecting retinal function was prolonged (p = 0.016) before surgery compared to aged-matched controls. After macula hole surgery, longstanding alteration of cone function reflected by mfERG and full-field ERG was verified 18 months after surgery. The prolonged cone 30-Hz flicker implicit time in the full-field ERG before surgery was significantly correlated to the ETDRS visual acuity 6 months postoperatively (p = 0.03). Preoperative evaluation of retinal function with multifocal ERG and full-field ERG improves the understanding of the retinal recovery process after macular hole surgery. The cone implicit time in full-field 30-Hz flicker ERG could be a valid predictor of long-term visual outcome, which may be useful for selecting patients suitable for surgery.

Retinoschisin (RS1), the product of RS1 located on the X chromosome, is expressed mainly in retina.¹ The 24-kDa RS1 encodes a highly conserved sequence motif termed the discoidin domain, which is a critical determinant of the structural and functional integrity of the retina.² Mutations in RS1 that lead to either complete loss of RS1 expression or its accumulation as a nonfunctional misfolded form are the underlying causes of X-linked retinoschisis (XLRS).³ This disorder, seen exclusively in young males, is characterized by splitting, or schisis, affecting all retinal layers. The precise molecular mechanism by which RS1 functions is still undefined. During development, there is a wave of RS1 expression beginning at the retinal surface and spreading progressively in more distal retinal layers as they differentiate.⁴ In adult mice, RS1 is expressed in all retinal neurons except horizontal cells,⁴ with a predominance in photoreceptor inner segments and bipolar cells.

Retinitis pigmentosa is said to be the most frequent reason for severe visual handicap among young people in Scandinavia today. Developments in the fields of electrophysiology and molecular genetics have increased our understanding of the pathophysiology of these disorders and have also improved our clinical competence, leading to a better understanding of the patient's visual handicap and his or her prognosis. This represents the first step towards fulfilling our plan for the future, which is ultimately to cure blindness caused by the different forms of hereditary retinal degeneration. This review is based on 20 years of research at the Department of Ophthalmology in Lund.