Abstract
Purpose :
To describe the clinical features of adRP due to a novel heterozygous deletion of PRPF31 identified in an Irish family following whole genome sequencing (WGS).
Methods :
Clinical tests performed included: ETDRS visual acuity, Goldmann perimetry, Full-field electroretinography (ERG), colour and autofluorescent fundus photography and optical coherence tomography. DNA samples underwent target capture next generation sequencing (NGS) of the exons of a panel of 260 inherited retinal disease-associated genes and WGS.
Results :
The proband is one of 4 siblings. Her mother, deceased at age 80, had no vision problems. Her maternal grandmother was known to have had low luminance and independent mobility issues by her 5th decade. The proband had poor night vision at age 17 years and problems with steps, pavement edges etc, suggestive of visual field loss at age 25. Best-corrected visual acuities were 6/15 (0.4) right eye and 6/12 (0.5) left eye at age 52 and 1/25 (0.04) right eye and 1/30 (0.03) by age 66, despite bilateral, technically successful, cataract surgery. Peripheral visual fields were concentrically constricted to within 10° of fixation, with preservation of small temporal islands bilaterally, at age 54 years. She retained the same central field in each eye over subsequent assessments, despite loss of the peripheral islands. At age 54 no convincing rod or cone full-field ERG responses were recordable. Target panel NGS failed to detect any convincing pathogenic sequence variants. However, subsequent WGS identified a large (c. 28kb) heterozygous deletion on chromosome 19, encompassing the whole of PRPF31. Cross deletion polymerase chain reaction and Sanger sequencing confirmed presence of this deletion in her unaffected mother and absence in her 3 unaffected siblings.
Conclusions :
Mutations in PRPF31 account for approximately 5% of adRP. Most are single base changes or deletions. Total deletion of the gene has been uncommonly reported. PRPF31 is an important component of the spliceosome, involved in pre-RNA splicing in RPE and photoreceptors. PRPF31 adRP is marked by reduced penetrance, as exemplified in this family. Total deletion of PRPF31 suggests haploinsufficiency as the causative mechanism and raises the possibility that gene replacement alone may be a therapeutic option, in contrast to a dominant-negative scenario where replacement alone is unlikely to result in benefit.
This is a 2021 ARVO Annual Meeting abstract.