Ophthalmic Genetics最新文献

Background: Corneal dystrophies (CDs) significantly affect quality of life. However, their progression and characteristics remain unclear. This study aimed to report a case of a unilateral variant of lattice corneal dystrophy (LCD) with c.1501C>A (p.P501T) and c.1733T>C (p.L578P) variants in the transforming growth factor-beta-induced (TGFBI) gene.

Case presentation: A 39-year-old Japanese woman presented with ocular pain and decreased visual acuity in the left eye. A slit-lamp examination of her left cornea revealed recurrent corneal erosion complicated by contact lens-associated infectious keratitis, fine lattice lines, and central corneal haze in the anterior stroma, with no opacities in the right cornea. In vivo confocal microscopic examination of the right eye showed highly reflective branching filaments in the corneal stroma, whereas the left cornea was unremarkable. Based on these clinical findings, we diagnosed the patient with unilateral LCD. The molecular genetic analysis revealed the TGFBI: a c.1501C>A (p.P501T) variant in exon 11 and the c.1733T>C (p.L578P) variant in exon 13.

Conclusion: A 39-year-old female patient with LCD with c.1501C>A (p.P501T) and c.1733T>C (p.L578P) TGFBI variants exhibited unilateral corneal findings, including recurrent corneal erosion, fine lattice lines, and central corneal haze in the anterior stroma. The study's findings could benefit CD treatment.

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(verification expired with no update), 14 (4.9%) trials which were terminated early and 6(2.1%) trials which were withdrawn.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.

Introduction: Variants in the CABP4 gene cause a phenotype to be included in the spectrum of congenital stationary night blindness, though some reports suggest that the clinical abnormalities are more accurately categorized as a synaptic disease of the cones and rods. We report a novel homozygous nonsense variant in CABP4 in a patient complaining of non-progressive reduced visual acuity and photophobia but not nyctalopia.

Methods: Complete ocular examination, fundus photographs, autofluorescence, optical coherence tomography, electroretinography, and targeted sequencing of known inherited retinal disease-associated genes.

Results: A 25-year-old man monitored for 13 years complains of a lifelong history of stable reduced visual acuity (20/150), impaired color vision (1 of 14 plates), small-amplitude nystagmus, and photophobia without nyctalopia. He is also hyperopic (+7D), and his electroretinography shows significantly reduced rod and cone responses. Targeted genetic analysis revealed a novel homozygous variant in the CABP4 gene at c.181C>T, p. (Gln61*) underlying his clinical presentation.

Conclusions: A novel variant in CABP4 is associated with stationary cone and rod dysfunction resulting in decreased acuity, color deficit, and photophobia, but not nyctalopia.

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.

Background: Prior research has shown a positive association of pseudoexfoliative glaucoma (PXG) in patients with non-melanoma skin cancer (NMSC), likely due to an increase in ultraviolet exposure associated with both. However, the role of NMSC as a genetic risk factor for PXG has not been examined. Thus, the goal of this study is to utilize Mendelian randomization with genome-wide association studies to evaluate for genetic causality while controlling for environmental confounders.

Methods: We conducted a MR using the inverse variance weighted method (MR-IVW) as our primary analysis. Genomic data was sourced from GWASs for patients with NMSC (10,382 cases, 208,410 controls) and PXG (1,515 cases and 210,201 controls), originating from the FinnGen Biobank.

Results: Despite previous association of history of NMSC with occurrence of PXG, we found no evidence for a causal association between SNPs associated with NMSC and risk of PXG following MR analysis (MR-IVW, odds ratio (OR): 0.98, 95% CI: 0.85-1.14, P = 0.87).

Conclusion: Here, we found no evidence for a causal association between SNPs associated with NMSC and the risk of PXG following a MR analysis.

Importance: Alström syndrome is a rare genetic disorder characterized by retinopathy and has life-threatening complications. Alström syndrome is frequently misdiagnosed or confused with other early childhood disorders with retinopathy.  Understanding the spectrum of ocular manifestations of Alström syndrome is essential for ophthalmologists to recognize the cause and institute-appropriate care for this disorder that requires multidisciplinary attention.

Objective: To quantify and summarize the common ocular findings of Alström syndrome.

Design: Case series, clinical exam data obtained from 2015 to 2023.

Setting: Semiannual multidisciplinary Alström syndrome clinics (2015-2023) at the Greater Baltimore Medical Center (GBMC), organized by Alström Syndrome International (ASI).

Participants: Forty-eight patients (38 children, 10 adults) with a known diagnosis of Alström syndrome participated in the semiannual multidisciplinary Alström syndrome clinics. Patients apply to be seen and are accepted based on need and capacity.

Intervention(s) or exposure(s): Not applicable.

Main outcome(s) and measure(s): Clinical ocular findings.

Results: Participants in this study had a median age of 8 years (15 months to 42 years). Visual acuity and progression of vision loss varied. The youngest patient who was legally blind was 2 years old. The oldest patient who maintained useful vision was 7 years old. All patients 8 years old or older were legally blind. Nystagmus (94%, 45 of 48) and photophobia (73%, 35 of 48) were the most common first presenting ocular symptoms in childhood. Retinal vascular attenuation (91%, 40 of 44) and retinal internal limiting membrane changes (68%, 30 of 44) were the most commonly documented retinal findings in both children and adults followed by optic nerve (ON) pallor and retinal pigment epithelium (RPE) mottling. Less than half of the children had ON pallor (38%, 14 of 37) and RPEmottling (38%, 14 of 37), while all adults had these two findings (100%, 7 of 7). Retinal pigment clumps were not common in children (11%, 4 of 37), while common in adults (86%, 6 of 7).

Conclusions and relevance: Knowledge of these ocular findings is key to promptly recognize Alström syndrome. The ocular phenotype of Alström syndrome is largely dependent on age, suggesting that low vision interventions and potential gene-based therapeutics should target children with this disorder.

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: Bardet-Biedl syndrome (BBS) is a rare syndromic ciliopathy characterized with retinal degeneration and a broad range of systemic features. Twenty-six BBS-associated genes have been identified to date and clinical genetic testing resolves around 80% of the cases. Two BBS cases unsolved by clinical genetic testing were recruited to identify causative variants using next-generation sequencing.

Methods: Genomic DNA of the probands from both families was extracted from peripheral blood. Whole genome or exome sequencing results were analyzed with comprehensive variant filtering on structural variants, single nucleotide variants (SNVs), insertions/deletions (indels).

Results: Family 1: A novel rare deletion NM_024649.5(BBS1): c.830 + 554_1110 + 1052del; p.(Asp278Metfs*3) was identified in the female proband in trans with a known pathogenic missense variant p.(Met390Arg). This 3k base pair (bp) deletion was predicted to cause a loss in exons 10-11, resulting in a premature stop codon. Family 2: Variant filtering in the male proband identified two rare (gnomAD AF < 0.01%) nonsense SNVs in trans in BBS9, NM_198428.3: c.724 G>T; p.(Gly242*) and c.966 G>A; p.(Trp322*), one of them being a novel pathogenic variant.

Conclusion: All the novel variants identified fell into the pathogenic variant classification following ACMG/AMP criteria. This report highlights the role of whole exome and genome sequencing in unsolved cases.

Purpose: Pathogenic variants in the CLDN19 gene are responsible for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) with ocular pathology (MIM *248190). Our objective was to delineate the ophthalmological and genetic manifestations of a patient with FHHNC and a pathogenic variant in CLDN19.

Case report: A 25-year-old woman presented with renal involvement and a best-corrected visual acuity of 20/25 in the right eye and finger-counting ability in the left eye. The patient exhibited high myopia, convergent strabismus, and chorioretinal atrophic plaques in the perifoveal and peripapillary areas. We conducted a comprehensive ophthalmological examination, including refraction, fundoscopy, color and autofluorescence retinography, optical coherence tomography, and electrophysiology tests. Additionally, next-generation sequencing was performed using Illumina NextSeq500. We identified a homozygous missense variant, c.59G>A p.Gly20Asp, in the CLDN19 gene as the cause of renal and ocular manifestations.

Conclusion: FHHNC is associated with various ocular alterations. The unique retinal disorders described in this article suggest a more favorable visual prognosis compared to those previously reported in the literature. Determining the phenotypic diversity of this disease may aid in the diagnosis and management of future cases.

Introduction: Bardet-Biedl Syndrome (BBS) is a ciliopathy causing developmental defects and progressive retinal dystrophy, whereas choroidal coloboma is a developmental defect causing structural deficiency in the posterior retina. Both are rarely reported together.

Methods: Here, we describe the phenotype and genotype of three unrelated patients with co-occurrence of Bardet-Biedl Syndrome and chorioretinal coloboma and review the pertinent literature.

Results: We describe three unrelated patients, with variable clinical features of Bardet Biedl syndrome. None had family history of BBS or coloboma. Each carried biallelic variants in BBS1, BBS9 and TTC8 gene, respectively. Two had unilateral chorioretinal coloboma, while one had bilateral chorioretinal coloboma.

Discussion: Although there may be other explanatory factors yet to be revealed, our data suggests that chorioretinal coloboma may be associated with BBS. The Hedgehog (Hh) signaling pathway, an intercellular communicator for development of the eye, is dependent on the primary cilia and plays a crucial role in the closure of the optic fissure. Both disorders therefore involve disruption of primary cilia function which may explain their association.