Ophthalmic Genetics最新文献

Introduction: Sector retinitis pigmentosa (RP) is an attenuated phenotype in comparison to classic pan-retinal disease. The inferior retina is most often affected, though other quadrants may become involved with time, particularly with more damaging genetic variants. Sector RP has been described in association with several known genotypes, most commonly RHO.

Methods: Case series of patients with a sector RP phenotype (and any affected family) and review of the literature.

Results: We describe two new genetic associations of sector RP: USH2A and PRPF31. Proband 1 had sector RP due to homozygous USH2A:c.13274C>T' variants while proband 2 had sector RP due to a heterozygous PRPF31:c.351dup variant. There was significant intrafamilial variability in each pedigree.

Discussion: Though both variants are previously reported, the phenotype in those reports was not consistent with sector RP. The current USH2A pedigree is the first reported with the c.13274C>T' variant homozygously, expressing a restricted, predominantly perivascular, sectoral RP. Non-syndromic USH2 genes have not previously been associated with sector RP. In the PRPF31 pedigree (c.351dup), the proband has restricted/sectoral disease but her daughter has classic pan-retinal RP. The cause of the attenuated phenotype and intrafamilial variability is unknown but could depend on several factors including occult modifier genes and environmental influences (e.g. light exposure to the inferior retina).

Background: Galloway-Mowat syndrome (GAMOS, OMIM: 251300) is a rare autosomal recessive (AR) neurodevelopmental disease, characterized by the combination of early-onset nephrotic syndrome and various central nervous system anomalies. The WD repeat-containing protein 73 (WDR73, OMIM: 616144) gene was the first gene found to be implicated in GAMOS1.

Methods: An AR family with parental consanguinity underwent comprehensive clinical and genetic analyses. In this study, the variant identified by whole exome sequencing was confirmed by Sanger sequencing and cosegregation analysis. A literature review was conducted to summarize previously reported cases of GAMOS1 caused by mutations in the WDR73 gene.

Results: The proband with GAMOS1 was a 3-year-old boy with normal renal function and typical characteristics of GAMOS1, including idiopathic nystagmus, agenesis of genitalia, persistent axial hypotonia, mild cerebellar atrophy, thinning of the corpus callosum, and brainstem hypoplasia. A novel homozygous frameshift mutation c.972_973dupCT (p.F325Sfs * 10) in the exon 8 of the WDR73 gene was identified in the proband. We summarized thirty-six previously reported GAMOS1 cases caused by mutations in the WDR73 gene.

Conclusion: We identified a novel homozygous frameshift mutation (c.972_973dupCT) in the WDR73 gene, causing AR GAMOS1 in a Chinese consanguineous family. The results are essential for further confirming the pathogenicity of WDR73 gene mutations and expanding the manifestation spectrum of GAMOS1.

Objective: This study reports the rare co-occurrence of CYP4V2 (causing Bietti crystalline dystrophy, BCD) and LRTOMT (causing nonsyndromic hearing loss) variants within a single family and analyzes their clinical correlation.

Methods: Exome sequencing was performed on three siblings with distinct clinical phenotypes. Sanger sequencing was used for variant confirmation. Although parental data was unavailable, the inheritance pattern was analyzed through co-segregation within the family.

Results: The proband, affected by both conditions, carried compound heterozygous variants in both CYP4V2 and LRTOMT genes. This correlated with more severe hearing loss compared to siblings carrying only LRTOMT variants. Siblings with isolated BCD or hearing loss carried variants only in the respective single gene. The findings suggest a double-compound heterozygous state in the proband.

Conclusion: This case highlights the genetic complexity of multisensory disorders, where the co-inheritance of variants in distinct genes may lead to a more severe phenotype. It underscores the need for comprehensive genetic testing and counseling in affected families.

Introduction: Oculo-auricular syndrome (OAS) is an extremely rare autosomal recessive disorder characterized by ocular anomalies and external ear malformations resulting from pathogenic HMX1 variants. In this study, we aimed to contribute to the literature by identifying a novel frameshift variant in the HMX1 gene.

Materials and methods: Genomic DNA was extracted from peripheral blood and analyzed by clinical exome sequencing using the SOPHiA DDM Clinical Exome Solution on an Illumina platform, with bioinformatic analysis performed according to ACMG guidelines. Identified variants were confirmed by Sanger sequencing using standard PCR amplification and capillary electrophoresis.

Case report: We describe a 5-year-3-month-old girl born to first-degree consanguineous parents, who previously underwent cataract surgery at 6 months of age. Clinical examination revealed iris coloboma, dysplastic ears including earlobe aplasia and hypoplastic helices, a high-arched palate. Clinical exome sequencing identified a novel homozygous frameshift variant in HMX1 (NM_018942.3:c.233_251dup, p.Ala85Argfs *53), which was confirmed by Sanger sequencing. Segregation analysis demonstrated heterozygous carrier status in the parents and healthy sibling.

Discussion: In this study, a novel frameshift variant in the HMX1 gene was identified in a patient with oculo-auricular syndrome, thereby contributing to the literature and further highlighting the importance of molecular testing.

The emergence of gene therapy for retinitis pigmentosa (RP) necessitates the evaluation and refinement of its diagnostic and management pathways. This expert opinion piece aims to identify gaps in the identification and management of patients with RP while proposing potential measures to mitigate these gaps. Insights were gathered from twelve eye care experts, including general ophthalmologists, pediatric ophthalmologists, optometrists, low vision specialists, genetic counselors, inherited retinal disease (IRD) specialists, and vitreoretinal surgeons, all of whom specialize in caring for patients with IRDs. Eleven experts participated in a live discussion, followed by offline input from all twelve, to synthesize the issues patients with RP face in the diagnostic and management process. From a diagnostic standpoint, the discussion identified lack of community recognition of RP signs and varied clinical presentations as barriers to timely and accurate diagnosis. Recommendations include greater education on symptoms and support resources, implementation of comprehensive eye exams for children and young adults, and improved patient engagement. Regarding management, the discussion highlighted delays between diagnosis and specialist referral, and logistical barriers to care. Recommendations include improved patient-provider communication, linking patients with coordinated care teams, promoting awareness of genetic testing and future treatment options, and increasing access to centers of excellence for genetic ophthalmology and low vision services. The current RP care pathway is hampered by lack of symptom recognition, appropriate testing routes, and resources. Addressing these barriers through a multidisciplinary approach is necessary to ensure that patients with RP receive optimal care and support before, during, and after management.

Purpose: Ocular Behcet disease (OBD) is a severe sight-threatening complication of Behcet disease (BD) with a poorly understood etiology, particularly in underrepresented populations such as Pakistan. It often arises from a combination of genetic predisposition, environmental triggers, and immune dysregulation. To address this gap, we explored genetic variants contributing to ocular involvement using whole-exome sequencing (WES).

Methods: Eleven clinically diagnosed BD patients were recruited, including ten with ocular symptoms such as uveitis, diplopia, and optic nerve involvement. WES was performed on five individuals, and rare, potentially damaging nonsynonymous variants were prioritized using in silico tools and annotated through ClinVar, MalaCards, GeneCards, and HGMD.

Results: Seventeen genes were found associated with ocular manifestations. Pathway enrichment (ClueGO) and regulatory variant analysis (RegulomeDB, score <3) were applied to identify pathways in OBD. Five genes, LRP2, NPHS1, DSCAM, MST1 and PAK2 were prioritized for their roles in immune regulation and maintaining ocular and neurovascular homeostasis. These genes carried variants with potential impact, while RegulomeDB highlighted two regulatory variants in LRP2.

Conclusion: This study provides the first genetic profile of OBD in Pakistani patients, identifies rare candidate genes of relevance, and establishes a foundation for larger confirmatory studies with implications for genetic screening.

Background: Inherited Retinal Diseases (IRDs) are a leading cause of genetic vision loss. Ophthalmic and genetic care for patients with IRDs requires extensive interdisciplinary coordination. In this retrospective cohort study, we compared timeliness and access to genetics services between a referral-based clinic model and an interdisciplinary clinic model.

Methods: 374 patients were evaluated for IRDs between January 2021 and February 2025. 239 (64%) were seen in a retina clinic with the option for referral to genetics services; 135 (35%) were seen in an interdisciplinary clinic offering same-day ophthalmology and genetic services. Outcomes were analyzed using chi-squared tests and general linear models. The primary outcomes were time to genetic diagnosis, genetic test completion, and genetic counseling utilization.

Results: Mean time to genetic diagnosis was significantly shorter in the interdisciplinary clinic (67 days) compared to the retina clinic (286 days) (p < 0.001). A higher proportion of those seen in the interdisciplinary model completed genetic testing (90.00% vs. 78.25%, p = 0.035) and saw a genetic counselor (64.66% vs. 48.12%, p < 0.001).

Conclusions: Interdisciplinary care expedited genetic diagnosis, increased genetic testing completion, and increased genetic counseling utilization in IRD evaluations. Timely genetic diagnosis may facilitate access to clinical trials, alleviate diagnostic uncertainty, and aid in planning for the future.

Purpose: We report a case of juvenile-onset cataracts due to variants in GCNT2, including a novel change within the GCNT2B isoform expressed exclusively in lens epithelial cells.

Methods: A retrospective chart review was conducted. The proband underwent serial ophthalmic examinations and next-generation sequencing (NGS) of 66 genes related to early-onset cataracts.

Results: An 8-year-old female (proband) was referred for ophthalmic evaluation for cataracts first diagnosed at age 6 years. Genetic testing identified two GCNT2 variants-one pathogenic variant (c.1040A > G;p.Tyr347Cys) in exon 3 and one variant of uncertain significance (c.677 G > T;p.Arg226Leu) in exon 1B.

Conclusion: In this case, bilateral juvenile-onset cataracts were presumed to be related to GCNT2 variants sometimes associated with congenital cataracts (OMIM *600429). Notably, this proband had juvenile-onset cataracts rather than the congenital presentation exclusively associated with GCNT2. Intragenic changes within exon 3 have been most frequently identified, while exon 1B has only been disrupted as part of a gene deletion. Here, the known pathogenic variant is within exon 3, while the variant in exon 1B represents a novel change. In summary, this case demonstrates GCNT2-related cataracts may present in childhood and expands the mutational spectrum through the first report of a missense variant in the lens-specific transcript GCNT2B.

Identification of an inherited RB1 pathogenic variant facilitates earlier diagnosis and improved outcomes for patients and at-risk relatives. Inheritance risk estimates, screening recommendations, and prenatal decision-making are complicated by RB1 variant-specific incomplete penetrance and parent-of-origin effect. This case report highlights a novel, deep intronic RB1 c.2212-170A > G variant identified through whole genome sequencing in a family with retinoblastoma exhibiting incomplete penetrance and a parent-of-origin effect. RNA analysis confirmed retention of intronic sequence (exonization), leading to unstable mRNA and/or truncated RB protein. This variant and the associated family history add to the existing body of literature to improve diagnostic genetic testing, clarify inheritance risks, and improve long-term outcomes for retinoblastoma patients.

To identify retinal genotype-phenotype correlations in CDH23-associated Usher syndrome (USH1D), review of clinical notes, and retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT). Subjects were grouped according to the combination of CDH23 variants-two loss-of-function (G1), one loss-of-function, and one non-loss-of-function (G2) or two non-loss-of-function variants (G3)-and parameters were compared. The mean age of onset (range) for patients in G1 was 8.9 (1-14), which was lower but not significantly different (p = 0.19). The mean LogMAR BCVA (range, ± SD) for G1 was 0.41 (0.2-0.9, ± 0.25), which was not significant (p = 0.1). Only one patient in G3 developed ellipsoid zone width (EZW) loss. Neither the mean outer nuclear layer (ONL) thickness at baseline, nor at the last vist were significantly different between groups (p = 0.84). The mean annual rate (± SD, 95% CI) of ONL thickness loss was 2.15 µm/y (± 2.2, [0.65-3.6]) in G1, 1.22 µm/y (± 1.6, [-1.3-3.8]) in G2 and 1.5 µm/y (± 1.5, [0.06-2.9]) in G3, which was not significantly different (p = 0.66). Although this data suggests a trend to a milder phenotype in patients with at least one non-LoF variant, none of the parameters assessed found statistically significant differences.