Ophthalmic Genetics最新文献

Microphthalmia and anophthalmia (M/A) are rare congenital eye anomalies with a birth prevalence of up to 1 in 10,000 births. The etiology of M/A can involve environmental and/or genetic factors, with a genetic origin identified in approximately 50% of cases through analysis of key genes. The transcription factor SOX2 is the most commonly implicated gene, accounting for around 15% of M/A cases. Recent studies have shown that the RNA-binding protein Rbm24 post-transcriptionally regulates Sox2 expression in mice and zebrafish, with Rbm24 null models exhibiting eye phenotypes in both species. Rbm24 can bind to Sox2 mRNA via three AU-Rich elements (AREs) located in its 3' untranslated region (UTR). In this study, we aimed to determine whether pathogenic variants within RBM24 or the SOX2 3'UTR AREs were present in a cohort of 50 individuals with M/A with no identified genetic cause for their condition. Despite the ocular defects observed in animal models, we did not detect any variant of interest in these candidate regions in our cohort. Although we cannot exclude the involvement of pathogenic variations in RBM24 or the SOX2 3'UTR AREs in ocular developmental defects, our study shows that they are unlikely to represent a frequent cause of M/A.

Introduction: X-linked inherited retinal diseases (XL-IRDs) are genetic disorders that typically present with higher disease burden in individuals assigned male at birth, often resulting in significant vision loss. Individuals assigned female at birth (AFAB) may also experience symptoms. Understanding the role of genetic counseling and testing in reproductive decision-making for AFAB individuals with XL-IRDs is crucial for improving reproductive empowerment.

Methods: This study surveyed AFAB individuals with a confirmed or family history of XL-IRDs. Eligible participants completed an anonymous online survey between July 2023 and November 2023, which collected data on genetic testing, counseling experiences, and the impact of these on reproductive decision making.

Results: Of the 118 survey respondents, 67% had confirmed genetics or a family history of CHM-related disease, 23% of RPGR/RP2, 5% of RS1, and 3% of NYX/CACNA1F. Fifty five percent of respondents would have preferred genetic testing earlier if it had been possible. Only 26 respondents (22.0%) received some sort of reproductive genetic counseling, the majority of which were counseled by a genetic counselor at a retinal dystrophy clinic. Most XX individuals with confirmed genetics or a family history of XL-IRDs had not received reproductive counseling about their diagnosis. However, their personal and familial experiences with an XL-IRD variably impacted their reproductive decision-making process.

Conclusion: Recognition that retinal dystrophy clinics are the primary location for XL-IRD reproductive risk counseling informs the timing and content of counseling by ophthalmic genetics providers and genetic counselors.

Background: The IFT140 gene is one of many genes involved in the synthesis of proteins needed for cilium function. Ciliopathies are a group of disorders associated with the dysfunction of ciliary structures and express as an individual organ system disease as well as multisystem disorders. Dysfunctional cilia typically manifest as pleiotropic clinical features, reflecting their widespread distribution and varied functionality.

Cases presentation: We present two cases: Case 1, a male with two pathological variations in IFT140 gene, a compound heterozygote, with kidney failure, retinal dystrophy, cardiomyopathy, and situs inversus and Case 2, a female with an IFT140 pathogenic homozygous variant, presented with nephrotic range proteinuria, retinitis pigmentosa, and pseudotumor cerebri.

Conclusions: As cilia dysfunction is known to cause pleiotropic clinical features due to the presence of cilia in different organs in the body, the clinical picture of the IFT140 mutation is also very heterogeneous. Our cases reveal unprecedented manifestations - LVNC, situs inversus, and pseudotumor cerebri - not previously documented in IFT140 mutation. These findings underscore the importance of genetic screening in ciliopathies.

Background: Retinoblastoma is the most common intraocular cancer in children, with significant variations in incidence and Survival. This study sought to evaluate nationwide retinoblastoma incidences and survival rates in the United States from 1996 to 2018.

Methods: We extracted data from the North American Association of Central Cancer Registries (NACCR) and the National Program of Cancer Registries between 1996 and 2018. Cases were stratified by sex, age, race, Hispanic origin, urban or rural origin, stage of the disease, and state of residence and compared by laterality. We applied SEER*Stat version 8.4.0.1 software for age-adjusted incidence rates (AAIR) and annual average per cent change (AAPC) and JoinPoint version 4.9.1.0 software to assess incidence trends. Survival trends were evaluated with JPSurv online software.

Results: The study comprised 5730 patients with a crude incidence rate (CIR) of 0.89 per million. The incidence declined from 29.6 per million in the first year of life to 16.5 in the second year. The CIR for unilateral and bilateral diseases were 0.61 and 0.27, respectively. Males had a slightly higher and significant crude incidence of 0.93 versus 0.86 for females. Hispanics had the highest rate of 1.48 in general. Treatment data revealed chemotherapy usage in 39% of unilateral and 78% of bilateral patients. The 5-year cumulative relative Survival did not significantly differ between unilateral (96.8%) and bilateral (97.0%) patients. A slight but significant annual decline in CIR was observed, with a trend toward an increase in the percentage of patients diagnosed in the first year of life.

Conclusions: This study indicated an overall decrease in incidence but a slight increase in early diagnosis. Findings underscore the need for consistent surveillance, early detection strategies, and personalized care to improve patient outcomes. The changes in the Survival in the unilateral disease require further investigations and mitigation strategies.

Introduction: Optic disc drusen (ODD) are believed to have a genetic predisposition, with autosomal dominant inheritance pattern with incomplete penetrance suggested through family pedigree analysis. ODD prevalence is higher in certain genetic disorders, such as pseudoxanthoma elasticum and retinitis pigmentosa. This study aimed to identify candidate genes potentially involved in the development of ODD.

Methods: Family members aged 18 years or older from families with ODD were included. Participants underwent optical coherence tomography of the optic nerve head, and blood samples were collected for whole-genome sequencing using the Illumina NovaSeq 6000 platform. Single nucleotide variants were identified with the Genome Analysis Toolkit (GATK) and filtered in VarSeq using a population frequency threshold of 1%. Selected genes were classified according to ACMG guidelines.

Results: A total of 10 families were included, three of which had more than two affected members. Thirty-three variants were identified, with the following genes selected for description: ABCC6, DDX50, TREX1, PLCB4, PTPRQ, LBR, RP1L1, and KRT3. The identified candidate genes showed a wide range of functions and are associated with different disorders. Of particular interest is ABCC6, which normally inhibits ectopic calcification.

Conclusion: We identified a list of candidate genes. Studies including larger ODD families are necessary to identify robust candidate genes.

Retinoblastoma (RB) is a common and potentially lethal cancer that primarily affects young children worldwide, with survival rates significantly varying between high- and low-income countries. This review aims to identify essential diagnostic markers for early diagnosis by investigating the molecular pathways associated with RB. The prevalence of RB cases is notably concentrated in Asia and Africa, contributing to a global survival rate estimate of less than 30%. Current management strategies involve complex, individualized treatment plans that consider cultural nuances, genetic abnormalities, staging, and the availability of medical resources. Recent studies suggest that circular RNAs (circRNAs) may serve as predictive and diagnostic biomarkers in the etiology of RB. This review examines the roles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circRNAs in RB, with the goal of improving survival rates, particularly in low- and middle-income countries. A deeper understanding of the molecular pathways of RB may facilitate the development of personalized treatment plans and targeted therapies. Elevated expression of circRNAs has been observed in most patient cases, and studies indicate that reducing specific circRNA production can inhibit tumor cell development and progression. Investigating the roles and mechanisms of circular RNAs in RB holds promise for future treatment approaches.

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.