-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the
gene is unexplained. We found three unrelated ...patients with a disease-causing
variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM).
was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years.
and
were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel
variants were identified. TEM of the lymphocytes of
and
showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the
-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of
mutations may be compensable and have variations.
Introduction
Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic
RPE65
-mediated inherited retinal dystrophies (IRD), a rare condition that ...starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) process recommended VN for patients in England and Wales. We assessed the cost-effectiveness of VN compared with best supportive care (BSC) in individuals with biallelic
RPE65
-mediated IRD in the UK.
Methods
A Markov model was developed to estimate the incremental cost per quality-adjusted life-year (QALY) gained for VN compared with BSC, from the perspective of the UK National Health Service and Personal Social Services. Phase III trial data were used to inform transition probabilities up to year 1, after which the treatment effect was assumed to be maintained for 40 years, followed by a decline in vision. A bespoke elicitation exercise involving clinical experts, patients and carers was conducted to estimate utility values for each model health state.
Results
At list price, VN is associated with incremental costs of £612,404 and incremental QALYs of 6.4, resulting in an incremental cost-effectiveness ratio (ICER) of £95,072 per QALY gained. Voretigene neparvovec is associated with a significant undiscounted QALY gain (20.5) and is therefore eligible for additional QALY weighting under the NICE HST process; an ICER of up to £205,000 per QALY gained could be considered cost-effective under this framework.
Conclusion
The results of the model show VN to be a cost-effective use of healthcare resources in the UK at list price. The availability of a commercial discount in the UK (as considered in the NICE appraisal) means that in reality the ICER will be even lower.
Plain Language Summary
Plain language summary available for this article.
Purpose
Mutation in the
USH2A
gene is the most common cause of inherited retinal dystrophy (IRD), including non-syndromic retinitis pigmentosa (RP) and Usher syndrome II (USH2). Gene editing and ...therapy targeting
USH2A
, especially the hotspot region, would benefit a large proportion of IRD patients. In this study, we comprehensively analyzed the genetic spectrum of the
USH2A
gene, aiming to identify global hot spot mutations in
USH2A
-related IRDs and differences in hot spot regions across continents.
Materials and methods
A retrospective
USH2A
-related IRD study was conducted, including our IRD cohort, and reported
USH2A
studies worldwide.
Results
A total of 3,972 mutated
USH2A
alleles of approximately 1,935 patients were collected from 33 cohort studies worldwide, containing 102 alleles of 51 patients in our IRD cohort. Mutations in exon 13 were the most common, reaching 18.4% globally and a higher frequency of 22% in America, 19.2% in Europe, and a lower 12% in East Asia. Pathogenic mutations that affected 10 of the 72 exons of
USH2A
, exon 2, exon 13, exon 41–43, exon 50, exon 54, exon 57, exon 61, and exon 63 in total were responsible for half of global
USH2A
mutant alleles. With base editors including adenine base editor (ABE), cytidine base editor (CBE), and glycosylase base editor (GBE), 76.3% of single nucleotide variations (SNVs) and 58% of all mutations in
USH2A
are correctable. Meantime, four novel pathogenic mutations were revealed in our IRD cohort, p. (Val1130Cysfs*72), p. (Ala2139fs*14), p. (Gly4139Arg), and p. (Val4166Cysfs*7).
Conclusion
In this study, we revealed four novel mutations, expanding the spectrum of
USH2A
mutations, and importantly presented global hotspot exons and mutations of
USH2A
as well as the proportion of SNVs that can be restored by different base editors, providing a perspective for exploring high-efficiency and broader-reaching gene editing and gene therapies.
Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive ...loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations.
Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients.
The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.
Importance
Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific ...retinal phenotypes. The diagnostic yield of targeted next‐generation sequencing may be increased by a reasonable preselection of RP‐patients.
Background
To systematically evaluate and compare features of genetically solved and unsolved RP‐patients.
Design
Retrospective, observational study.
Participants
One‐hundred and twelve consecutive RP‐patients who underwent extensive molecular genetic analysis.
Methods
Characterization of patients based on multimodal imaging and medical history.
Main Outcome Measures
Differences between genetically solved and unsolved RP‐patients.
Results
Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease‐onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years‐of‐age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing.
Conclusions and Relevance
The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP‐patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease‐causing mutations and may impact patient counselling.
Background
Inherited retinal dystrophy (IRD) is a group of irreversible retinal degenerative disorders with significant genotypic and phenotypic heterogeneity, which cause difficulty in making a ...precise clinical diagnosis. Furthermore, the mutation spectrum of IRD in Taiwan remains unknown. Therefore, our study focused on investigating the spectrum of mutations among Taiwanese families with IRD using targeted exome sequencing (TES) technology.
Methods
We recruited a total of 60 unrelated Taiwanese families with IRD; most of them were retinitis pigmentosa. We employed TES to investigate 284 candidate genes. Bioinformatics analysis, Sanger sequencing‐based co‐segregation testing, and computational assessment were performed to validate each mutation and its pathogenicity. The genotype‐phenotype correlation was analysed in all patients with mutations defined in the guidelines provided by the American College of Medical Genetics.
Results
We successfully identified genetic causes in 32 families (detection rate of 53.3%). Among them, 16 had a sporadic inheritance (16/36, 44.4%); eight had an autosomal recessive inheritance (8/14, 57.1%); four had an autosomal dominant inheritance (4/5, 80%); four had an X‐linked inheritance (4/5, 80%). Among 38 pathological mutations in 19 known genes, 20 mutations are reported here for the first time. Novel mutation spectrum and genotype‐phenotype correlations were revealed as well.
Conclusion
Here we achieved a detection rate of 53.3% and elucidated the mutation spectrum in Taiwanese families with IRD for the first time. The results indicated that CYP4V2 and USH2A might be the most common pathogenic genes in IRD patients in Taiwan.
To present the retinal and systemic findings in two siblings with compound heterozygous MPDZ variants that were found to have different chorioretinal manifestations. Materials and Methods: Two ...sibling patients underwent comprehensive ophthalmic examination, including ophthalmoscopy, fundus photography, optical coherence tomography (OCT), and genetic testing by whole exome sequencing.
A 4-year-old male presented with intermittent exotropia and decreased vision in both eyes. Ophthalmologic examination was notable for macular colobomas and far temporal chorioretinal atrophy in both eyes. OCT of the macula in both eyes demonstrated a caldera with severe retinal and choroidal thinning. Fluorescein angiography of the central macula showed hypofluorescence with persistence of deep choroidal vessels. An ocular gene panel was nondiagnostic, but subsequent whole-exome sequencing noted compound heterozygous, likely pathogenic MPDZ variants (c.3100C>T p.(Arg1034*) from father and c.747 + 2T>G p.(?) from mother). His older brother, a 9-year-old male, had a history of macrocephaly but had not undergone further workup. On exam, he had a visual acuity of 20/25 in the right eye and 20/40 in the left eye and was found to have subtle changes in the foveal reflex of both eyes. OCT revealed thinning of the outer nuclear layer (ONL) temporal to the fovea bilaterally. Sanger sequencing revealed he was positive for the same two MPDZ variants.
MPDZ variants have been described in cases of congenital hydrocephalus with varying ophthalmologic manifestations. We present a case series describing retinal phenotypes associated with MPDZ variants in a single family through multimodal imaging.
Pathogenic variants in the CEP78 gene can present as atypical Usher syndrome or as retinitis pigmentosa. Here, we present a review of all reported cases of CEP78 variants in the literature to date ...and present a novel variant of CEP78, c.1261_1262delinsA, in a consanguineous northern Finnish family with two individuals.
Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on CEP78 was published in the year 2007, and the publications from the years 2007-2021 were included.
A large gene panel identified a homozygous CEP78 c.1261_1262delinsA variant in two affected siblings. In addition to the classical signs of retinitis pigmentosa, both siblings had large round atrophic spots in the mid periphery, and hyperautofluorescence of the macula. Patient 1 had age-related hearing impairment; patient 2 had normal hearing. In total, 20 articles have been published about CEP78. Eight of these papers report patient data with the affected individuals typically having retinal dystrophy combined with sensorineural hearing impairment, classified as atypical Usher syndrome.
Here, we present a comprehensive review of CEP78 and expand the knowledge of pathogenic CEP78 variants and the phenotypic variety.
Next-generation sequencing, also known as massively paralleled sequencing, offers an unprecedented opportunity to study disease mechanisms of inherited retinal dystrophies: a dramatic change from a ...few years ago. The specific involvement of the retina and the manageable number of genes to sequence make inherited retinal dystrophies an attractive model to study genotype-phenotype correlations. Costs are reducing rapidly and the current overall mutation detection rate of approximately 60% offers real potential for personalized medicine and treatments. This report addresses the challenges ahead, which include: better understanding of the mutation mechanisms of syndromic genes in apparent non-syndromic patients; finding mutations in patients who have tested negative or inconclusive; better variant calling, especially for intronic and synonymous variants; more precise genotype-phenotype correlations and making genetic testing more broadly accessible.
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