Cellular Imaging of the Tapetal-Like Reflex in Carriers of RPGR-Associated Retinopathy

Kalitzeos, Angelos; Samra, Ranjit; Kasilian, Melissa; Tee, James; Strampe, Margaret R.; Langlo, Christopher S; Webster, Andrew R.; Dubra, Alfredo; Carroll, Joseph; Michaelides, Michel

doi:10.1097/iae.0000000000001965

Cited by 27 publications

(17 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fovea is typically spared. Recently, cellular resolution provided by adaptive optics scanning laser ophthalmoscope at points identified with a radial reflex pattern has shown features of reduced cone density, increased inner segment diameters, and increased rod outer segment reflectivity [11].…”

Section: Resultsmentioning

confidence: 99%

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy

Nanda

Salvetti

Clouston

et al. 2018

Genes

View full text Add to dashboard Cite

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p < 0.0001). Skewed X-inactivation can result in severely affected carrier females—in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.

show abstract

Section: Resultsmentioning

confidence: 99%

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy

Nanda

Salvetti

Clouston

et al. 2018

Genes

View full text Add to dashboard Cite

show abstract

“…Fundus ophthalmic examination of his daughter, Case 14, revealed a radiating pattern of hyperreflectivity that manifests as patchy radial streaks on fundoscopy, referred to as the tapetal-like reflex, a characteristic phenotype commonly observed in RPGR carriers ( Fig. 1b) [17,18]. Targeted sequencing of the RPGR gene detected the heterozygous c.2405_ 2406delAG (p.Glu802Glyfs*32) variant in the proband and his daughter.…”

Section: Rpgrmentioning

confidence: 99%

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

Cho

Carvalho

Tanaka

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background: Whole exome sequencing (WES) allows for an unbiased search of the genetic cause of a disease. Employing it as a first-tier genetic testing can be favored due to the associated lower incremental cost per diagnosis compared to when using it later in the diagnostic pathway. However, there are technical limitations of WES that can lead to inaccurate negative variant callings. Our study presents these limitations through a re-evaluation of negative WES results using subsequent tests primarily driven by fundoscopic findings. These tests included targeted gene testing, inherited retinal gene panels, whole genome sequencing (WGS), and array comparative genomic hybridization. Results: Subsequent genetic testing guided by fundoscopy findings identified the following variant types causing retinitis pigmentosa that were not detected by WES: frameshift deletion and nonsense variants in the RPGR gene, 353bp Alu repeat insertions in the MAK gene, and large exonic deletion variants in the EYS and PRPF31 genes. Deep intronic variants in the ABCA4 gene causing Stargardt disease and the GUCY2D gene causing Leber congenital amaurosis were also identified. Conclusions: Negative WES analyses inconsistent with the phenotype should raise clinical suspicion. Subsequent genetic testing may detect genetic variants missed by WES and can make patients eligible for gene replacement therapy and upcoming clinical trials. When phenotypic findings support a genetic etiology, negative WES results should be followed by targeted gene sequencing, array based approach or whole genome sequencing.

show abstract

“…XLRP caused by pathogenic RPGR variants is one of the most severe forms of RP, with early onset of disease, night blindness, myopia, severe generalized rod and cone dysfunction, and progression to legal blindness by the third or fourth decade 3,21 . Carrier females are mostly asymptomatic or mildly affected with characteristic fundus features and electrophysiological abnormalities 22 , although the severity of carriers varies.…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants

et al. 2019

View full text Add to dashboard Cite

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of X-linked inherited retinal disorder (IRD). We herein describe the clinical and genetic features of 14 patients from 13 Japanese families harboring RPGR variants in a nationwide cohort. Comprehensive ophthalmological examinations were performed to classify the patients into one of the phenotype subgroups: retinitis pigmentosa (RP) and cone rod dystrophy (CORD). The mean age of onset/at examination was 13.8/38.1 years (range, 0–50/11–72), respectively. The mean visual acuity in the right/left eye was 0.43/0.43 (range, 0.1–1.7/−0.08–1.52) LogMAR unit. Eight patients had RP, and six had CORD. Whole-exome sequencing with target analyses identified 13 RPGR variants in 730 families with IRD, including 8 novel variants. An association between the phenotype subgroup and the position of variants (cutoff of amino acid 950) was revealed. To conclude, the clinical and genetic spectrum of RPGR-associated retinal disorder was first illustrated in a Japanese population, with a high proportion of novel variants. These results suggest the distinct genetic background of RPGR in the Japanese population, in which the genotype–phenotype association was affirmed. This evidence should be helpful monitoring and counseling patients and in selecting patients for future therapeutic trials.

show abstract

Cellular Imaging of the Tapetal-Like Reflex in Carriers of RPGR-Associated Retinopathy

Cited by 27 publications

References 45 publications

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants

Contact Info

Product

Resources

About