Study Outlines Genetic, Ophthalmologic Characteristics of Rare Retinitis Pigmentosa Subtype

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In a longitudinal cohort study, researchers identified 17 seemingly novel variants of the PDE6A retinitis pigmentosa gene, suggesting it may be amenable to gene therapy.

In a longitudinal cohort study, researchers identified 17 seemingly novel variants of the PDE6A retinitis pigmentosa (RP) gene, suggesting it may be amenable to gene therapy. Results of the study were published in JAMA Ophthalmology.

RP is a degenerative retinal disease that causes severe visual impairment and visual acuity loss as a result of progressive degeneration of the rod and cone photoreceptors, according to the authors. The hereditary disease manifests with early-onset nyctalopia, while best-corrected visual acuity remains relatively well preserved until macular involvement. Eventually, macular edema and/or photoreceptor atrophy causes central visual acuity loss in patients.

So far, sequence variations in 89 genes are known to be associated with the disease. However, “in 1995, the gene encoding for the α subunit of the rod photoreceptor cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6A) was identified as the seventh RP locus,” the researchers wrote. In North America, the PDE6A gene appears to account for disease in less than 4% of families with autosomal recessive RP.

To determine the clinical features and course of RP associated with biallelic sequence variations in the PDE6A gene, the researchers carried out a prospective, longitudinal, observational cohort study between January 2001 and December 2019.


All participants underwent a comprehensive ophthalmological examination at the Centre for Ophthalmology of the University of Tübingen, Germany, and had a confirmed genetic diagnosis of PDE6A-associated RP.

Fifty-seven patients (114 eyes) from 44 families were included in the analysis, and the majority (56%) were female. “Given that PDE6A-associated RP is such a rare genetic subtype of RP, the size of this cohort is uniquely large,” the researchers wrote.

At baseline, the mean (SD) age was 40 (14) years, while the mean follow-up time for all participants was 2.9 (2.1) years.

The nvestigators found:

  • 30 patients were homozygous for disease-causing alleles
  • 27 patients were heterozygous for 2 PDE6A variants each
  • The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M)
  • Mean best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50)
  • Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)
  • 69 of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy)
  • The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S)

“Our clinical findings are thus in line with the fact that c.998 + 1G>A;p.? is considered a null allele, in contrast with c.304C>A;p.(R102S),” the authors noted.

In addition, because PDE6 is rod specific, it would be more promising to treat regions outside the macula with high rod density early in patients’ lives.

Because the disease was highly symmetrical between right and left eyes and visual impairment was mild or moderate in 90% of patients, the researchers hypothesize these clinical findings provide a window of opportunity for gene therapy in individuals with PDE6A-associated RP.


Kuehlewein L, Zobor D, Andreasson SO, et al. Clinical phenotype and course of PDE6A- associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial. JAMA Ophthalmol. Published online October 15, 2020. doi: 10.1001/jamaophthalmol.2020.4206