Ophthalmic Genetics最新文献

Background: Oculodentodigital dysplasia (ODDD) is a rare syndrome that causes a constellation of facial, ophthalmic, dental, and limb abnormalities. Variants in the gap junction alpha-1 (GJA1) gene have been described in patients with ODDD. Hereby we present the ocular manifestations in a patient with recessive ODDD due to a novel homozygous frameshift variant in GJA1.

Material and methods: Detailed ophthalmic manifestation and clinical features of disease were documented through external color photography and ultrasound biomicroscopy (UBM). Genetic testing was performed through a congenital heart disease panel.

Results: A six-year-old girl was referred for ophthalmic evaluation in the setting of numerous syndromic features compatible with ODDD. Clinical features included nasal thinning, alar hypoplasia, hypotrichosis, microdontia and enamel hypoplasia. Ocular manifestations included microcornea, microphthalmia, posterior synechiae, cataract, and persistent hyperplastic primary vitreous. Genetic testing revealed a novel homozygous variant in the GJA1 gene, c.565del p.(Arg189Glufs *35). This variant disrupts the fourth helical transmembrane domain of the protein as well as its C-terminal cytoplasmic tail.

Conclusion: Here we describe the clinical and ocular manifestations of a Brazilian patient with ODDD, report a novel frameshift homozygous variant in GJA1, and contribute to the ongoing expansion of scientific knowledge regarding ODDD.

Purpose: To assess the impact of MitoQ, a mitochondria-targeted antioxidant, on viability of human corneal endothelial cell (hCEnC) lines expressing SLC4A11 mutations associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy type 4 (FECD4).

Methods: SLC4A11 wildtype (SLC4A11^WT) and mutant (SLC4A11^MU) hCEnC lines were created to express either SLC4A11 variant 2 (V2) or variant 3 (V3) by stable transduction of SLC4A11^-/- hCEnC-21T with lentiviruses containing either SLC4A11^WT or one of the following mutations: V2 (V3) mutants c.374 G>A (c.326 G>A) (CHED), c.1813C>T (c.1765C>T) (CHED), c.2263C>T (c.2215C>T) (CHED), or c.2224 G>A (c.2176 G>A) (FECD4). A SLC4A11^{-/- empty} hCEnC line was created by stable transduction of SLC4A11^-/- hCEnC-21T with an empty lentiviral plasmid. Cell viability was measured by exposing MitoQ treated and untreated cells to oxidative stress agent tert-butyl hydroperoxide (tBH) followed by performing XTT assays and spectrophotometry.

Results: SLC4A11^{-/- empty}, SLC4A11 V2^WT, and SLC4A11 V3^WT hCEnC exposed to ≤0.01 μM MitoQ retained over 90% of the viability of untreated SLC4A11^{-/- empty} hCEnC. When treated with MitoQ, SLC4A11^{-/- empty} was able to demonstrate partial restoration of cell viability. All CHED-associated mutant hCEnC lines treated with 0.01 μM MitoQ demonstrated increased viability compared to untreated following exposure to tBH. The FECD4-associated mutant hCEnC line treated with 0.01 μM MitoQ showed no significant increase in cell viability compared to untreated following exposure to tBH.

Conclusions: Media supplementation with antioxidant MitoQ has beneficial effects on cell viability in hCEnC harboring CHED-associated SLC4A11 mutations following exposure to tBH-induced oxidative stress.

Aim: Leber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one's vision loss and managing their own uncertainty about potential vision loss and its familial implications.

Method: We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs.

Results: Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup.

Conclusion: To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss.

Background: Retinoblastoma is diagnosed and treated without biopsy based solely on appearance (with the indirect ophthalmoscope and imaging). More than 20 benign ophthalmic disorders resemble retinoblastoma and errors in diagnosis continue to be made worldwide. A better noninvasive method for distinguishing retinoblastoma from pseudo retinoblastoma is needed.

Methods: RetCam imaging of retinoblastoma and pseudo retinoblastoma from the largest retinoblastoma center in the U.S. (Memorial Sloan Kettering Cancer Center, New York, NY) were used for this study. We used several neural networks (ResNet-18, ResNet-34, ResNet-50, ResNet-101, ResNet-152, and a Vision Image Transformer, or VIT), using 80% of images for training, 10% for validation, and 10% for testing.

Results: Two thousand eight hundred eighty-two RetCam images from patients with retinoblastoma at diagnosis, 1,970 images from pseudo retinoblastoma at diagnosis, and 804 normal pediatric fundus images were included. The highest sensitivity (98.6%) was obtained with a ResNet-101 model, as were the highest accuracy and F1 scores of 97.3% and 97.7%. The highest specificity (97.0%) and precision (97.0%) was attained with a ResNet-152 model.

Conclusion: Our machine learning algorithm successfully distinguished retinoblastoma from retinoblastoma with high specificity and sensitivity and if implemented worldwide will prevent hundreds of eyes from incorrectly being surgically removed yearly.

Background: Pathogenic variants in KIF11, a kinesin family gene, cause MCLMR and FEVR. In MCLMR, chorioretinal atrophy is present in the majority of cases and can be a helpful diagnostic sign.

Cases: We present the cases of two patients with chorioretinal atrophy and microcephaly who carry novel KIF11 mutations. Both patients have relatively good central vision similar inferior lacunae of retinal atrophy with relative sparing of the foveal center with.

Conclusion: Two cases with classic features of MCLMR have foveal sparing that expands the associated spectrum of ocular findings.

Background: The phenotypic variability of inherited conditions can be due to several factors including environmental, epigenetic, and genetic. One of those genetic factors is the presence of modifying loci which alter the phenotypic expression of a primary disease or phenotype-causing variant. Modifiers are known to affect penetrance, dominance, expressivity, and pleiotropy of disease.

Methods: We review the literature to highlight the impact of modifiers on inherited retinal diseases.

Results: Modifiers have been identified or associated with phenotypic variation in many inherited retinal diseases including retinitis pigmentosa and Stargardt disease. Despite being notoriously difficult to identify, proposed candidate modifiers have been identified using multiple methods including GWAS, family and population studies, and variant calling methods.

Conclusions: Overall, modifiers present themselves as an interesting target for further understanding of underlying disease pathways that could ultimately lead to therapeutic targets.

Purpose: This study sought to analyze the effect of allele mutations and gene functions specific to glaucoma susceptibility among Africans.

Methods: Potentially relevant studies were retrieved from major bibliographic databases (PubMed, Scopus, and Web of Science). Data were extracted and study-specific estimates were meta-analyzed using various models to obtain pooled results.

Results: A total of 11 studies were included in the study. The studies included a total of 3,191 cases with glaucoma and 3,013 controls across all variants. There is no association between the E396E variants of the myocilin (MYOC) gene and an increased likelihood of susceptibility to POAG (OR: 0.91 [95% CI 0.42 to 1.97]). The R141L variant of the Lysyl Oxidase Like 1 (LOXL1) gene is associated with an approximately 3-fold increased likelihood of susceptibility to exfoliative syndrome/exfoliative glaucoma (XFS/XFG) (OR: 2.68 [95% CI 0.04 to 198.94]). There is no association between the G153D variant of the LOXL1 gene and an increased likelihood of susceptibility to XFS/XFG (OR: 0.42 [95% CI 0.02 to 7.65]). The rs59892895*C variant of the Amyloid Beta Precursor Protein Binding Family B Member 2 (APBB2) is associated with a 34% increased likelihood of susceptibility to POAG (OR: 1.34 [95% CI 1.13 to 1.58]).

Conclusion: Although progress has been made in understanding the genetic basis of the pathogenesis of glaucoma, several gene mutations related to glaucoma pathogenesis in Africans are yet to be discovered, especially those associated with the pathogenesis of POAG, the most prevalent glaucoma subtype in Africa.

Purpose: We present the case of a newborn with right anophthalmia, left congenital cystic eye, and two novel variants in the ALDH1A3 gene. This report provides a comprehensive discussion of the clinical presentation, management strategies, and long-term follow-up for this rare condition.

Methods: A thorough ophthalmic examination was performed. Genetic analysis employed next-generation sequencing targeting a panel of 50 genes implicated in microphthalmia, anophthalmia, and coloboma.

Results: A one-day-old female, born to unrelated parents, was referred due to bilateral ocular malformations. Prenatal ultrasound in the third trimester had raised concerns about a congenital ocular developmental anomaly, and fetal magnetic resonance imaging suggested right anophthalmia and left eye aphakia. Postnatal examination revealed an empty right orbital cavity and a bluish lesion bulging from the left lower lid. Orbital imaging confirmed the bilateral absence of ocular structures and identified a cystic lesion in the left orbit. At three months of age, an orbital expander was placed in the right anophthalmic socket. At fifteen months, the left orbital cyst was excised due to rapid growth. Histopathological analysis revealed neuroglial tissue lining the cyst, consistent with a congenital cystic eye. A delay in psychomotor development has been noted, but no other signs of systemic conditions have been identified to date. Genetic testing identified two previously unreported ALDH1A3 variants: c.1036C>A (p.Pro346Thr) and c.981C>G (p.Tyr327*).

Conclusion: Our study identifies two previously unreported variants in the ALDH1A3 gene, broadening the understanding of its phenotypic spectrum. We report the first association between ALDH1A3 variants and congenital cystic eye.

Introduction: Round atrophic macular scars with a hyperpigmented rim in an otherwise healthy child are characteristic for prior ocular toxoplasmosis infection, the most common etiology of self-resolved retinitis in immunocompetent patients. However, a specific homozygous gene mutation (NM_148960: CLDN19:c.263T>A; p.Val88Glu) can result in a similar phenotype.

Methods: Retrospective case series (2018-2023) of children homozygous for the gene mutation CLDN19:c.263T>A; p.Val88Glu. Five children (3 families) were identified.

Results: All 5 identified affected children had been referred for reduced vision and had bilateral central macular scars. Three children (2 families) were originally diagnosed with presumed prior ocular toxoplasmosis infection. All 5 children have stable ophthalmic finding over 5-6 years of follow-up. Although other CLDN19 mutations are associated with early-onset pediatric renal disease, none from this cohort with this specific CLDN19 variant has evidence for renal disease to date.

Conclusions: CLDN19-related maculopathy can resemble and be mistaken as prior ocular toxoplasmosis infection. Unlike other CLDN19 mutations, the homozygous variant in this cohort has not been associated with renal disease to date. Genetic maculopathy should be considered in children with macular scars presumed to be related to prior ocular toxoplasmosis infection, particularly when the scarring is bilateral or familial.

Background: Pseudoxanthoma elasticum (PXE) is characterized by aberrant calcification of elastic tissues throughout the body causing varying degrees of skin, cardiac, and ocular disease. Although PXE is classically regarded as an autosomal recessive disease, recent reports have demonstrated a haploinsufficiency phenotype, in which carriers of monoallelic ATP-binding cassette transporter (ABCC6) gene mutations demonstrate mild manifestations of PXE. In this case report, we describe a patient with a monoallelic ABCC6 mutation and atypical angioid streaks.

Materials and methods: Case report.

Observations: A 31-year-old male with a history of paroxysmal tachycardia and right ventricular enlargement presented to the Eye Emergency Department complaining of bilateral eye pain with occasional flashes and bitemporal headaches. Family history was notable for unspecified heart disease in his father but no ocular disease. Best-corrected visual acuity was 20/20 in both eyes. Posterior segment examination demonstrated linear hypopigmented lesions radiating from the superior arcades of both eyes. Fundus autofluorescence of the lesions demonstrated speckled hypo- and hyperautofluorescence and fluorescein angiography revealed window defects consistent with atypical angioid streaks. Genetic testing was positive for a heterozygous c.2889C>A (p.Cys963*) mutation in the ABCC6 gene.

Conclusions and importance: The current case demonstrates the potential for PXE carriers to display both systemic and ophthalmic manifestations of the disease. Individuals with known or suspected monoallelic ABCC6 mutations may benefit from genetic counseling and regular examination.