Ophthalmic Genetics最新文献

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.

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.

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.

Objective: To describe the current status of clinical trials of genetic eye diseases with identified molecular targets for future areas of research.

Method: Data analysis of the clinical trials database on clinicaltrials.gov with keywords for eight common, genetically tractable inherited eye diseases and their common molecular targets was performed during the period from 20 March 2021 to 31 December 2023.

Results: Two hundred and eighty-eight trials involving our keywords have been identified, excluding 25 (8.7%) trials which were unknown (verification expired with no update), 14 (4.9%) trials which were terminated early and 6(2.1%) trials which were withdrawn. In total there were 243 (84.4%) trials included. Out of the 243 trials, 120 trials were completed, 76 trials were active and still open to recruitment and 44 trials were active without any more recruitment on the way. There were only 32 (13.2%) trials with posted results.

Conclusions: A low percentage of results were posted for completed trials. However, current and future clinical trials in the genetic eye diseases with molecular targets identified, have a promising future. The results of these trials will enhance and allow a better understanding of the potential to develop treatments for these conditions.

Background: Geleophysic dysplasia (GD) and Weill-Marchesani syndrome (WMS) are two rare genetic disorders that are classified as acromelic dysplasias and have many common features that overlap clinically and genetically in some patients. Both diseases are characterized by acromelic features, including short stature, brachydactyly, joint limitations, and cardiac involvement. WMS is distinguished from GD mainly by ocular abnormalities, including high myopia, microspherophakia, ectopia lentis, and glaucoma and the absence of the life-threatening airway stenosis and early lethality. These two syndromes are allelic diseases of the FBN1 gene, with the gene families including A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) and latent transforming growth factor-beta-binding protein (LTBP). Although the ADAMTSL2 gene has been associated only with GD within the acromelic dysplasias, there have been reports of patients with ADAMTSL2-related GD exhibiting ocular abnormalities that resemble WMS.

Methods and results: We present a 24-year-old female patient with microspherophakia, ectopia lentis, myopia, short stature, joint stiffness, thick skin, short hands and feet, and cardiac valve disease consistent with WMS. The virtual panel analysis, including WMS and GD-related genes, revealed a homozygous c.493 G>A (p.Ala165Thr) variant in the ADAMTSL2 gene (NM_014694.4), which has been previously reported in a geleophysic dysplasia patient.

Conclusions: Mounting evidence suggests that GD and WMS may be allelic diseases of the ADAMTSL2 gene.

Background: Heterogeneity can impact biomarker identification. Thus, we investigated the somatic copy number alterations (SCNAs) of individual tumor cells in the vitreous humor of a retinoblastoma patient using single-cell whole-genome profiling and explored the genomic concordance among vitreous and aqueous humor, vitreous seeds, and tumor.

Methods: Aqueous humor (AH), vitreous humor (VH), and tumor biopsy were obtained from an enucleated globe with retinoblastoma and vitreous seeding. Micromanipulation was used to manually isolate 39 live single tumor cells from vitreous seeds harvested from the VH. The SCNA profiles of these individual cells were generated via whole-genome sequencing and analyzed alongside profiles from the tumor mass and cell-free DNA (cfDNA) from AH and VH.

Results: Heatmap of VH single-cell SCNA profiles demonstrates heterogeneity among individual vitreous seeds with one clearly dominant subclone (23 of 37 cells). The SCNA profiles from the cells in this subclone demonstrate an average concordance of 98% with cfDNA profiles from acellular AH and VH and with the tumor profile.

Conclusions: Our findings reveal some heterogeneity among single-cell SCNA profiles in individual VH seeds. Despite this heterogeneity, the dominant vitreous subclone exhibits extremely (>98%) high concordance with the SCNA profile from tumor and AH, suggesting AH cfDNA is representative of the dominant genomic subclone. This may facilitate tumoral biomarker identification via the AH. This preliminary work supports the potential of applying single-cell technology to VH seeds in retinoblastoma as a platform to study tumor subclones, which may provide insight into the genomic complexity of disease.

Purpose: The biallelic variant of MAB21L1 has previously been documented in conjunction with the autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG). The purpose of this study was to investigate the gene-disease association of MAB21L1 and the newly discovered autosomal dominant (AD) microphthalmia.

Methods: We report the presence of an exceptionally rare missense variant in a single allele of the Arg51 codon of MAB21L1 among four individuals from a single family diagnosed with microphthalmia, which suggesting an autosomal dominant inheritance pattern. Subsequently, based on comprehensive literature review, we identified another 13 families that have reported cases of autosomal dominant microphthalmos.

Results: Genotype-phenotype analysis revealed that patients with a single allele missense variant in MAB21L1 exhibited solely eye abnormalities. This starkly diverged from the clinical presentation of COFG, typified by the concurrent occurrence of ocular and extraocular symptoms stemming from the biallelic variant in MAB21L1. Our findings revealed that the heterozygous pathogenic variant in MAB21L1 resulted in the emergence of autosomal dominant microphthalmia. By combining these genetic and experimental evidence, the clinical validity of MAB21L1 and the emerging autosomal dominant microphthalmia can be regarded as moderate.

Conclusion: In summary, there is sufficient convincing evidence to prove that MAB21L1 is a novel pathogenic gene responsible for autosomal dominant microphthalmia, thus offering valuable insights for precise diagnosis and targeted therapeutic interventions in cases of microphthalmia.

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.

Background: BCL6 co-repressor (BCOR) gene variants are involved in oculofaciocardiodental (OFCD) syndrome, acute myeloid leukaemia, renal tumours, and photoreceptor degenerative diseases. Here, we describe a British family with a pathogenic heterozygous variant in the BCOR gene causing congenital nuclear cataract.

Methods: Whole-exome sequencing was conducted on an individual affected by X-linked dominant congenital cataract in a three-generation family to establish the underlying genetic basis. Bioinformatics analysis confirmed the variants with damaging pathogenicity scores.

Results: A novel likely pathogenic frameshift variant BCOR NM_001123385.1: c.3621del; p.Lys1207AsnfsTer31, was identified and found to co-segregate with the disease in this family.

Conclusions: This is apparently the first report of a variant in BCOR causing X-linked dominant congenital cataract which is potentially isolated or presenting with a remarkably mild systemic phenotype. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of BCOR variants.

Background: This case report explores the relationship between genetics and phenotypic variability in autosomal dominant vitreoretinochoroidopathy (ADVIRC). The study focuses on a case presenting a novel mutation in the BEST1 gene and its phenotype in the case's relatives, shedding light on the structural and functional intricacies underlying this rare ophthalmologic disorder.

Case presentation: A 33-year-old female presented for consultation with a history of bilateral retinal damage accompanied by a complaint of decreased visual acuity, progressive visual field deficit, and night blindness over the past year. Ophthalmic examination revealed a distinctive phenotype, including fibrillar vitreous, pigmented cells, and atrophic hyperpigmented retina in the periphery which was suggestive of a diagnosis of ADVIRC. Genetic testing revealed a heterozygous c.1101-1 G>T variant in BEST1, a novel splice site mutation. Functional analysis confirmed its impact on pre-mRNA splicing, resulting in an in-frame deletion (p(Ser367_Asn579del)). Family investigation revealed varying degrees of ophthalmologic impairment in the patient's mother and half-sister, both carrying the same mutation.

Conclusions: This case report provides the first clinical description of the c.1101-1 G>T mutation in the BEST1 gene associated with ADVIRC. The presence of intrafamilial variability, as evidenced by the differing clinical features observed in the index case and her half-sister, suggests the potential involvement of mechanisms influencing phenotype expression.Abbreviation: ADVIRC : autosomal dominant vitreoretinochoroidopathy; RNA : ribonucleic acid; RPE : retinal pigment epithelium.