Ophthalmic Genetics最新文献

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.

Donnai‑Barrow syndrome (DBS) is an ultra-rare autosomal recessive disorder with fewer than 100 reported cases. Affected individuals have biallelic LRP2 (megalin) loss‑of‑function variants and varying clinical features that can include craniofacial anomalies, sensorineural hearing loss, renal tubular dysfunction, and distinctive ocular features. This article reviews the genetic and developmental basis of the syndrome and outlines its key ophthalmic manifestations of high myopia, retinal detachment, oculofacial findings of hypertelorism and iris coloboma, and optic nerve head anomalies. Additionally, this article describes diagnostic strategies including prenatal imaging and molecular testing and summarizes currently available management approaches drawn largely from case reports given the condition's rarity. By consolidating the limited literature and illustrative clinical examples, this review offers practicing ophthalmologists a concise reference for early recognition and multidisciplinary care of these patients.

Background: Oculoskeletodental syndrome (OCSKD) is a rare autosomal recessive ciliopathy caused by PIK3C2A loss-of-function variants, characterized by ocular, skeletal, and dental anomalies. Ocular findings most commonly include cataract and secondary glaucoma; however, high axial myopia and megalocornea have not been previously reported in the literature.

Case presentation: We report a 2-year-old girl with OCSKD who presented with severe high axial myopia, bilateral megalocornea, lamellar cataracts, and developmental delay. Systemic evaluation revealed short stature and dental enamel hypoplasia. Clinical exome sequencing and whole mitochondrial genome sequencing identified a homozygous pathogenic variant in exon 8 PIK3C2A(NM_002645.4;ENST000000265970.11):c.1733_1736del(p.lle578LysfsTer3); NC_000011.10:g.17136594_17136597del [GRCh38]. The variant was classified as pathogenic and predicted to be damaging by MutationTaster2. Prenatal Sanger variant analysis testing of amniotic fluid in a fetus (to be the sibling of the index patient) showed the same variant in heterozygous form, confirming autosomal recessive inheritance.

Conclusion: This case highlights phenotypic variability in PIK3C2A-related oculoskeletodental syndrome and raises the possibility of additional ocular involvement. Early molecular diagnosis enables accurate genetic counseling and supports targeted prenatal testing in affected families.

Purpose: To characterize an undiagnosed patient with retinal dystrophy, ataxia, and neurodevelopmental delay.

Materials and methods: A 13-year-old female patient presenting with nystagmus and defective vision since infancy, underwent ophthalmological, neurological examination, ultra-wide field fundus photography, autofluorescence and electroretinogram. Exome sequencing (ES) was done followed by segregation analysis. Analysis of the glycosylation profiles of plasma glycoprotein markers was performed using immunoblotting.

Results: Visual acuity was counting fingers; her fundus examination and imaging revealed an Early Childhood Onset Retinal Dystrophy (ECORD) phenotype. Ichthyosiform skin lesions were noted, and neurological assessment revealed proximal limb-girdle pattern of weakness, hyperactive reflexes, extensor plantar responses with evidence of cerebellar dysfunction. ES uncovered a homozygous, likely pathogenic missense variant c.509A > G, p.(Tyr170Cys) in SRD5A3 gene. In silico functional analysis prediction tools supported the variant being deleterious. Segregation analysis confirmed carrier status of parents and the brother, while plasma glycoprotein markers for N- and O-glycosylation showed an aberrant glycosylation profile.

Conclusion: We report a variant in the SRD3A5 gene reported for the first time in a case of CDG. We are expanding the neurophenotypic spectrum by reporting proximal limb-girdle pattern of weakness combined with diffusely brisk reflexes and bilateral extensor plantar responses suggestive of corticospinal or neuromuscular axis involvement.