Ophthalmic Genetics最新文献

Background: Disease-causing variants in the KCNV2 gene are associated with "cone dystrophy with supernormal rod responses," a rare autosomal recessive retinal dystrophy. There is no previous report of hypomorphic variants in the disease.

Material and methods: Medical history, genetic testing, ocular examination, high-resolution retinal imaging including adaptive optics scanning light ophthalmoscopy (AOSLO), and functional assessments.

Results: A 16-year-old male with mild cone-rod dystrophy presented with reduced central vision and photophobia. Genetic testing showed two variants in KCNV2, c.614_617dupAGCG (p.207AlafsTer166) and c.854T>G (p.Met285Arg), the latter which was previously considered benign. Electrophysiological assessment revealed the pathognomic electroretinogram waveforms associated with KCNV2-retinopathy. Optical coherence tomography showed discrete focal ellipsoid zone disruption, while fundus autofluorescence was normal. Non-waveguiding cones corresponding to areas of loss of photoreceptor integrity were visible on adaptive optics scanning light ophthalmoscopy. Retinal sensitivity and fixation were relatively preserved, with a demonstrable deterioration after 14 months of follow-up.

Conclusions: We provide functional and structural evidence that the variant M285R is disease-causing if associated with a loss-of-function variant. To the best of our knowledge, this is the first hypomorphic allele reported in KCNV2.

Background: GAPO syndrome is a rare autosomal recessive disorder characterized by the acronym of growth retardation, alopecia, pseudo-anodontia and progressive optic atrophy. While the genetic alteration of the ANTXR1 gene has been known for its cause, the full range of its clinical and genetic manifestations is not well explored due to the syndrome's extreme rarity.

Materials/methods: We report two children born to a non-consanguineous parent in India with classical features of GAPO syndrome. The whole exome sequencing analysis (WES) was performed in both siblings, and the parent's genetic and clinical status was determined. The identified variation was characterized in silico using homology-based protein modelling.

Results: In WES analysis, a homozygous ANTXR1 gene indel variant c. 151_152 + 2delAAGT (p.Lys51fs) was identified in both siblings. The parents were identified as the carriers of the ANTXR1 variant. Additionally, they also displayed mild GAPO-related facial and glaucomatous features. In silico analysis and homology-based ANTXR1 protein structure illustrate a frameshift and the subsequent premature truncation of the protein.

Conclusions: Our reports contribute to the comprehension of GAPO syndrome within the Indian context describing an ANTXR1 novel variant causing premature protein truncation. WES-based genetic testing can significantly aid in expertly diagnosing GAPO syndrome. In the present case scenario, a variable penetrance of ANTXR1 variation was acknowledged as the carrier parents also had a mild degree of GAPO-related features. Future reports that include parental clinical diagnosis can offer further insights in this context.

Purpose: Occult macular dystrophy (OMD) is a cause of visual loss in young adults with a grossly normal fundus appearance. It is considered an autosomal dominant disorder, related to heterozygous pathogenic variants in the gene RP1L1. The purpose of this study is to report a biallelic form of the disease.

Results: A 29-year-old female had undergone neurological workup and ophthalmic examinations for transient visual loss in her left eye over the past two years but there was no definitive diagnosis. The best-corrected visual acuity was 20/30, 20/20. Indirect ophthalmoscopy with a 78D lens revealed subtle central retinal pigment epithelium mottling and optical coherence tomography confirmed subtle central thickening of the ellipsoid zone. Full-field electroretinography was normal, but pattern electroretinography showed decreased p50 responses. OMD was suspected. Retinal gene panel testing was significant only for a homozygous variant in RP1L1 (NM_178857.6: c.3571 G>T; p.Glu1191*). The parents and older brother were unavailable for segregation analysis. By history they did not have visual complaints other than a need for glasses.

Conclusions: This report presents the clinical and genetic findings of a biallelic form of OMD associated with a novel pathogenic variant in RP1L1. It would be of interest to carefully assess macular function in heterozygotes with this variant.

Purpose: The MEFV gene encodes pyrin, a protein linked to increased severity of symptoms in Familial Mediterranean Fever (FMF). We consider that inflammation due to MEFV variants would increase eye inflammation and damage aqueous humor regulation. The present study is the first analysis investigating a MEFV (E148Q) variant as a marker protecting from glaucoma.

Methods: In this prospective clinical analyze, we performed detailed gene sequencing focusing on 22 specific regions of the pyrin (MEFV) gene. The study involved two distinct groups: individuals diagnosed with glaucoma (n = 200) and control subjects without glaucoma (n = 100). Both groups were carefully selected to exclude individuals with symptoms or a previous diagnosis of Familial Mediterranean Fever (FMF). The diagnosis of glaucoma for each participant was rigorously established through comprehensive direct ophthalmic examinations.

Results: A significant odds ratio for protection against glaucoma was found in carriers of the subclinical E148Q allele (OR:2.22; 95%CI: 1.098-4.485). No significant differences were found for other variants. One mutant E148Q-allele could decrease the probability of glaucoma development by approximately 68,9%. We observed no differences in the genotype frequency between glaucoma and healthy for the other MEFV gene variants.

Conclusion: The pyrin variant of the MEFV gene resulting in a subclinical phenotype appears to reduce the incidence of glaucoma, and heterozygous pyrin (MEFV) E148Q allele carriers confer protection against glaucoma. It is important to consider the limitations arising from the relatively small number of studies conducted on this topic.

Introduction: Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS.

Materials and methods: Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1).

Results: In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels.

Conclusions: Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Purpose: To assess age at 1^st central retinal vein occlusion (CRVO) in carriers ≤ 45 years old of the methylenetetrahydrofolate reductase (MTHFR) C667T genotype compared to heterozygous and wild type, and to identify predictors of age at CRVO.

Methods: Retrospective cohort study consisting of 18 MTHFR TT, 23 MTHFR TC and 28 MTHFR CC participants; information regarding age, sex, age at CRVO, history of dyslipidaemia, hypertension, smoking and plasma HC measured by immunoassay were collected.

Results: Age at CRVO was lower in MTHFR TT than MTHFR TC and CC (32 ± 6 vs 38 ± 5 vs 37 ± 6 years, respectively, p = 0.005); plasma HC was higher in MTHFR TT than in the other genotypes [14.4 (10.8, 19.6) vs 10.4 ((8.6,12.5) vs 8.5 ((7.5,9.8) μmol/l, p = 0.0002). Smoking (cigarettes/day) independently predicted age at CRVO (p = 0.039) and plasma HC (p = 0.005); smoking status (yes/no) predicted ischemic CRVO (p = 0.01) that was more common in the MTHFR TT group (p = 0.006).

Conclusions: Carriers of the MTHFR TT genotype ≤ 45 years old develop their 1^st CRVO on average 5 years earlier than the MTHFR CC genotype; smoking contributes to the prematurity and severity of CRVO in MTHFR TT carriers.

Background: To describe the phenotype and genotype of 10 Brazilian patients with variants in MFRP, posterior microphthalmos and retinal findings.

Methods: Complete ophthalmological evaluation was done at 4 different Brazilian centers. Genetic analysis was performed using commercial next generation sequencing panels for inherited retinal disorders.

Results: Ages of the patients ranged from 10 to 65 years and visual acuities from 0,05 to no perception of light. All were hyperopes (+4,25 to + 17,50) with a short axial length (14,4 mm to 18 mm). Common posterior segment features, though not present in all, were optic disc drusen (5/10), foveoschisis (5/10) and retinal pigmentary changes (8/10). Isolated patients presented with macular atrophy, serous retinal detachment, and chorioretinal folds. The most common variant in MFRP found in our patients was a deletion in exon 5 (c.498delC; p.Asn267Thrfs *25), present in all except 2 patients. Other variants found were c.523C>T (p.Gln175*), c.298delG (p.Ala100Argfs *37), c.666del (p.Thr223Argfs *83) and the novel variant c.257C>A (p.Ala86Asp).

Conclusions: This is the first report of Brazilian patients with posterior microphthalmos and pathogenic variants in MFRP and the first describe of the variant p.Ala86Asp in literature. Our cases confirm the previously reported phenotype of high hyperopia, optic disc drusen, alterations in foveal architecture, retinal pigmentary changes with loss of photoreceptor function and visual field constriction. Report of such a rare condition is important to increase awareness to the phenotype of posterior microphthalmia with associated retinal conditions.

Identification of pathogenic RB1 variants aids in the clinical management of families with retinoblastoma. We routinely screen DNA for RB1 variants, but transcript analysis can also be used for variant screening, and to help decide variant pathogenicity. DNA was screened by conformation analysis followed by Sanger sequencing. Large deletion/insertions were detected by polymorphism analysis, MLPA and quantitative-PCR. Methylation-specific PCR was used to detect hypermethylation. RNA screening was performed when a DNA pathogenic variant was missing, or to determine effects on splicing.Two hundred and thirteen small coding variants were predicted to affect splicing in 207 patients. Splice donor (sd) variants were nearly twice as frequent as splice acceptor (sa) with the most affected positions being sd + 1 and sa-1. Some missense and nonsense codons altered splicing, while some splice consensus variants did not. Large deletion/insertions can disrupt splicing, but RNA analysis showed that some of these are more complex than indicated by DNA testing. RNA screening found pathogenic variants in 53.8% of samples where DNA analysis did not. RB1 splicing is altered by changes at consensus splice sites, some missense and nonsense codons, deep intronic changes and large deletion/insertions. Common alternatively spliced transcripts may complicate analysis. An effective molecular screening strategy would include RNA analysis to help determine pathogenicity.

Background: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype.

Materials and methods: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES).

Results: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals.

Conclusions: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.