Ophthalmic Genetics最新文献

Introduction: Retinoblastoma is initiated by inactivation of RB1 gene, but additional alterations may be required for tumor progression. Substitution and INDEL variants in different genes, aside RB1, are infrequent, while large copy number variants (CNVs) like gains on 1q, 2p, 6p and loss on 16q are common, they include oncogenes or tumor suppressors and are typical of retinoblastoma.

Aim: To provide the molecular profile that is useful for prognosis and understanding of retinoblastoma development.

Methods: To identify genomic variants in six retinoblastoma tumors whole exome sequencing and informatic analysis were performed.

Results: RB1 was the only gene with nonsense or frameshift mutations. SNVs in other 11 genes were missense and at non-canonical splice-sites, all nonpathogenic. CNVs, similar to those reported, were identified in all retinoblastoma tumors. The most frequent were 1q gain and 16q loss. Additionally, deletions were identified on 13q, including RB1 gene, and on the X chromosome, including BCOR gene, the most frequently mutated, after RB1, in retinoblastoma. The number of CNVs detected in each tumor was between 1 and 7, depending on the age at diagnosis.

Conclusion: The analysis of genomic alterations in retinoblastoma is useful to understand the severity of tumor progression and to apply appropriate treatments.

Case Summary The patient is a 42-year-old female who presented with a de novo missense variant in the PRPS1 gene. Her phenotype includes asymmetric retinal dystrophy with sensory esotropia, congenital sensorineural hearing loss, neuropathy, and severe tremors with recent-onset ataxia. This contributes a new presentation of ophthalmic and neurological findings to the literature.

Purpose: Usher syndrome, a common form of syndromic inherited retinal dystrophy in the Arabian Gulf, has not been molecularly defined in the United Arab Emirates. The current study addresses this gap in knowledge.

Methods: A retrospective case series of Emirati patients referred to the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi who (1) were clinically diagnosed with Usher syndrome and underwent genetic testing (whole exome sequencing, 2019 to 2023, inclusive) and (2) were identified to have biallelic pathogenic variants in Usher syndrome genes during the same time period.

Results: Ten probands (thirteen patients) were identified-seven probands (nine patients) with clinically diagnosed Usher syndrome and three additional probands (four patients) with biallelic homozygous USH2A variants. Among the seven probands initially diagnosed with Usher syndrome, six had different homozygous variants (three in MYO7A, one in ADGRV1, and one in CLRN1), one had dual diagnoses rather than Usher syndrome (i.e. separate cause for retinal dystrophy and deafness), and one had no identifiable genetic cause. Regarding the three additional probands identified with homozygous USH2A variants, all three had retinitis pigmentosa only rather than Usher syndrome and all three had different variants.

Discussion: Clinically diagnosed Usher syndrome was genetically heterogenous without evidence for founder effect in this Emirati cohort. MYO7A was the most common associated gene. Dual diagnosis rather than single cause can mimic Usher syndrome. Homozygous USH2A variants were not identified as a cause for Usher syndrome in this cohort but were a recurrent cause for retinitis pigmentosa without hearing impairment and without founder effect.

Introduction: Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs. To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease.

Methods: We retrospectively recruited 7 unrelated individuals who underwent genetic testing (targeted gene panel or whole genome sequencing) and were found to carry CEP250 pathogenic variants.

Results: Most patients (5/7) exhibit both retinal dystrophy and SNHL. Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation. All patients harbored isolated truncating variants.

Discussion: CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction. The disease may begin with ocular features or hearing loss. We strongly recommend genetic analysis of classical and atypical Usher related-genes, in patients with isolated retinal dystrophy or SNHL. We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely. The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy.

Introduction: ABCA4 and PRPH2-related diseases are both phenotypically heterogeneous and clinically difficult to differentiate. There may be examination and imaging features that can aid in establishing a clinical diagnosis.

Methods: A single-center, retrospective, consecutive case series including patients with a molecular confirmation of pathologic variants in either the ABCA4 or PRPH2 were included. Chi-square analysis, Fisher exact test, and Student's t-test comparing prevalence of specific examination and imaging features between ABCA4 and PRPH2.

Results: Of the 127 eyes from 64 patients included, the ABCA4 group was more significantly associated with peripapillary sparing on both fundus imaging (73% vs. 40%; p = 0.006) and FAF (71% vs. 44%; p = 0.025), macular (64% vs. 12%; p < 0.001) and peripheral pisciform flecks (22% vs. 3.6%; p = 0.025). The PRPH2 group was more highly associated with macular chorioretinal atrophy (86% vs. 55%; p = 0.003).

Conclusions: Peripapillary sparing and pisciform flecks are more highly associated with ABCA4-related disease, while macular chorioretinal atrophy is more highly associated with PRPH2-related disease. Logistic regression demonstrates that bull's eye maculopathy and macular flecks are predictive of the ABCA4 genotype.

Introduction: Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disorder classically characterized by central nervous system and renal abnormalities. Optic atrophy has been reported as a common ophthalmic feature, and other characteristics, including nystagmus, strabismus, oculomotor apraxia, and retinopathy have been reported; however, data on retinal involvement and dysfunction is limited. In this case report, we aim to describe retinal findings in a female adolescent diagnosed with GAMOS due to a homozygous variant in the WDR73 gene.

Methods: A comprehensive ophthalmologic examination, including dilated fundus examination, fundus photography, electroretinogram (ERG), and optical coherence tomography (OCT), was performed. Systemic findings were obtained from medical records.

Results: The patient's visual testing was significant for oculomotor apraxia, large angle esotropia, and cross fixation. On fundus examination, bilateral optic nerve pallor and retinal vessel attenuation were noted. OCT revealed bilateral retinal thinning. ERG demonstrated non-recordable rod and cone responses.

Discussion: This case report describes multimodal imaging findings in a patient diagnosed with GAMOS due to biallelic homozygous variants in the WDR73 gene with comparison of retinal findings and ERG results to previously reported cases. Furthermore, we present OCT and fundus images for the first time in the literature.

Background: Cone dystrophy is a heterogeneous hereditary retinal disorder with disease symptoms appearing in the late first or early second decades of life.

Methods: A consanguineous Pakistani family with three affected individuals underwent detailed clinical and genetic investigation.

Results: The proband, a 63-years old male, showed severely reduced day vision, a visual acuity of counting fingers (CF), color vision deficiency, high myopia and photophobia. Fundus images showed bilateral peripapillary atrophy, bilateral dull foveal reflex, tilted disc, tessellated fundus, and hyperfluorescence at the peripheral superior temporal arcade and leak at an early stage. OCT macula and angiography findings suggested traction near the disc in the right eye and sub-retinal fluid at the fovea in the left eye. Retinal layers were normal toward the periphery but disorganized near the disc. Full visual field tests showed bilateral central scotoma, while single visual field tests indicated bilateral generalized depression of the visual field. The proband showed normal bilateral intraocular pressure, normal choroidal vessels, and unremarkable anterior segment. Exome sequencing identified a novel homozygous missense variant (POC1B:NM_172240.3:c.1391T>C;p.L464P) in the proband. Existing evidence supported pathogenicity of the identified variant in the family.

Conclusion: In conclusion, we document a first-ever Pakistani family with POC1B-related cone dystrophy.

Background: Primary open-angle glaucoma (POAG) is a subtype of glaucoma that accounts for 60%~70% of all cases. Its pathogenic mechanism is intricate and its pathogenic process is concealed. Numerous significant biological processes associated with POAG continue to be elucidated.

Methods: In this study, by exploring the expression data of POAG tissues and normal tissues, we mined the regulatory lncRNAs and mRNAs closely associated with the pathogenesis and progression of POAG by exploring a regulatory network of competing endogenous RNA (ceRNA), established by integrating gene expression data with the known lncRNA-miRNA and miRNA-mRNA-regulatory interactions. The key regulatory pathways and regulatory elements of POAG were identified by topological analysis. Simultaneously, the exome data of 28 cases with POAG and healthy controls were analyzed to identify high-frequency mutations and genes.

Results: A total of 2712 differentially expressed genes were identified, including 1828 mRNAs and 884 lncRNAs. Network analysis suggested that lncRNAs such as HAGLR, HOTAIR and MIR29B2CHG, and mRNAs such as PPP6R3, BMPR2 and CFL2, may be involved in the onset and progression of POAG. In addition, 55 mutations with potential pathogenicity were identified.

Conclusion: These genes and mutations provide novel potential genetic heterogeneity and genetic susceptibility of POAG, as well as fresh suggestions for elucidating the molecular mechanism underlying the pathogenesis of POAG.

Introduction: Wolfram syndrome due to bi-allelic variants in WFS1 and mono-allelic Wolfram-like syndrome have variable ocular and syndromic associations. In this report, eight patients are described.

Methods: A retrospective observational case series with detailed ophthalmic and systemic phenotyping, optical coherence tomography (OCT), and neuroimaging. Molecular investigations included gene panel and targeted Sanger sequencing.

Results: Eight patients (six female, two male) from six families were diagnosed with optic atrophy at a mean age of 15.5 ± 6.2 years (range 8-23) with mean follow-up of 3.2 ± 3.4 years (range 1.5-12.1). Three were asymptomatic. Mean presenting visual acuity was 0.31 ± 0.26 logMAR (Snellen equivalent 20/40). Diabetes mellitus was present in five patients (detected after screening in one), sensorineural hearing loss in five and diabetes insipidus in one. Other systemic features included psychiatric disorders in four patients and bladder dysfunction in three patients. OCT demonstrated marked nerve fiber layer loss in all patients. In dominant disease, macular OCT demonstrated a linear splitting abnormality of the outer plexiform layer (OPL) not found in recessive disease. Three novel variants in WFS1 were identified. After identification of the p.Val606Gly variant in three Māori patients including one with cone-rod retinal dystrophy, a reference database of 80 Māori/Pasifika patients with retinal dystrophy/optic atrophy was interrogated. This identified the variant in 10 patients with disease attributed to other genes.

Conclusions: In Wolfram syndrome, systemic features are variable. Pathognomonic OPL lamination is associated with dominant disease. Early recognition of potentially syndromic optic atrophy allows prompt diagnosis of unrecognized diabetes mellitus.

Background: Keratoconus (KC) is an asymmetrical bilateral corneal ectasia, of which the pathogenesis is unknown. Moreover, genetic factors play an important role. We reported ophthalmic findings in a Chinese family with monozygotic twins with KC to describe the clinical features and identify genetic variants.

Methods: Comprehensive ophthalmic clinical assessments and examinations, including history, slit-lamp biomicroscopy, best-corrected visual acuity, corneal topography, anterior segment optical coherence tomography, and corneal biomechanics, were carried out on the twins and their parents. Whole-genome sequencing (WGS) was performed to identify variants in this family. SIFT, PolyPhen2, MutationTaster, and CADD were used to predict the effect of amino acid substitutions on the affected protein.

Results: The twins presented typical KC features. However, their mother did not meet the criteria for a KC diagnosis but exhibited KC subclinical manifestations. After screening, 12 potentially pathogenic variants in 10 genes were identified in both twins and emerged as candidate variants for this family. These genes included 1 previously reported KC-associated variant (ZNF469, c.4384 G>A); 8 variants in 6 KC-associated genes (GRHPR, c.337 G>A, c.862_863del; COL6A1, c.920 G>A; FLG, c.8753C>G; HSPG2, c.9503C>T; KRT82, c.1306 G>A; SCN9A, c.5702_5706del, c.641 G>A); and 3 variants in 3 non-KC-associated genes (PDE6G, c.6C>A; HAL, c.1724C>T; AGBL1, c.2381 G>A).

Conclusions: The accumulation of these potentially pathogenic variants in twins may have caused KC in these twins. These results expand the spectrum of KC candidate variants and provide a basis for further studies on KC.