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PURPOSE: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1 -related retinopathy and other retinal degenerations. METHODS: Medical charts and OCT images of 28 patients with either autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa RP1 -related retinopathy were reviewed. Outer retina microcavitations were defined as hyporeflective OCT structures of at least 30 µ m in diameter between the ellipsoid zone and retinal pigment epithelium. Comparison was made based on the following metrics: (1) functional measures including best-corrected visual acuity and color discrimination errors on D-15 test; and (2) structural measures, including central subfield, average macular thickness, and preserved transfoveal ellipsoid zone width. Mann-Whitney tests were used for comparisons with significance set at P < 0.05. The specificity of microcavitations for RP1 -related retinopathy was estimated against 26 patients with non- RP1 retinitis pigmentosa. RESULTS: Among 15 included patients, microcavitations were found in at least one eye of all patients with arRP and 7/12 (58%) of patients with adRP. Patients with adRP and microcavitations were older at the time of examination (51 vs. 43 years of age; P = 0.04) and their eyes demonstrated worse best-corrected visual acuity (0.09 vs. 0 logMAR; P = 0.008), reduced central subfield (256 vs. 293 µ m; P = 0.01), average macular thickness (241 vs. 270 µ m; P = 0.02), and shorter transfoveal ellipsoid zone widths (1.67 vs. 4.98 mm; P < 0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1 -related retinopathy. CONCLUSION: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1 -related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.
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Retinose Pigmentar , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Tomografia de Coerência Óptica/métodos , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Acuidade Visual/fisiologia , Estudos Retrospectivos , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Idoso , Epitélio Pigmentado da Retina/patologia , Adulto Jovem , Adolescente , Proteínas Associadas aos MicrotúbulosRESUMO
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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Defeitos da Visão Cromática , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Humanos , Mutação , Células Fotorreceptoras Retinianas ConesRESUMO
Molecular variant interpretation lacks disease gene-specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2-related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin-2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease-enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2-related retinopathy. Large disease gene-specific cohorts permit gene modeling for hotspot and disease-enrichment analysis, providing novel variant classification evidence, including for novel missense variants.
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Estudos de Associação Genética , Periferinas/genética , Doenças Retinianas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Sistema de Registros , Adulto JovemRESUMO
Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high-throughput screening of 38 known coloboma-associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand-binding domain, was a missense change in the highly conserved DNA-binding domain predicted to affect the protein's DNA-binding ability. In vitro studies revealed lower steady-state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild-type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA-binding domain could result in human disease.
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Coloboma/diagnóstico , Coloboma/genética , Proteínas de Ligação a DNA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Domínios e Motivos de Interação entre Proteínas , Receptores do Ácido Retinoico/metabolismo , Adulto , Animais , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/química , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Receptores do Ácido Retinoico/química , Relação Estrutura-Atividade , Peixe-ZebraRESUMO
Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross-referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.
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Coroideremia/genética , Oftalmopatias Hereditárias/genética , Retinose Pigmentar/genética , Doença de Stargardt/genética , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Coroideremia/diagnóstico , Coroideremia/epidemiologia , Coroideremia/terapia , Proteínas da Matriz Extracelular/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/epidemiologia , Oftalmopatias Hereditárias/terapia , Proteínas do Olho/genética , Feminino , Testes Genéticos/tendências , Terapia Genética/tendências , Humanos , Masculino , Periferinas/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/terapia , Doença de Stargardt/diagnóstico , Doença de Stargardt/epidemiologia , Doença de Stargardt/terapiaAssuntos
Segmento Anterior do Olho/anormalidades , Coloboma/diagnóstico , Segmento Posterior do Olho/anormalidades , Úvea/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Coloboma/fisiopatologia , Feminino , Humanos , Masculino , Microftalmia/diagnóstico , Microftalmia/fisiopatologia , Pessoa de Meia-Idade , Miopia/diagnóstico , Miopia/fisiopatologia , Acuidade Visual/fisiologia , Adulto JovemRESUMO
BACKGROUND: Variations in the protocadherin gene FAT1 have recently been associated with a syndrome that includes coloboma, facial dysmorphism, renal failure, syndactyly, and other developmental defects. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: This non-dysmorphic, intellectually normal 51-year-old woman presented with bilateral colobomata and renal failure of unclear etiology, and asymmetric sensorineural hearing loss. Family history was notable for multiple family members with various forms of cancer. Whole exome sequencing revealed a homozygous frame shift variant in FAT1, predicted to truncate the FAT1 protein at the furthest position in the protein structure published to date in a patient with coloboma. CONCLUSIONS: This case provides further evidence of the pleiotropic effects of FAT1 in optic fissure closure and kidney function. Also, because this variant is in the last exon, it would be anticipated to escape nonsense-mediated decay, opening the possibility that the protein is made and expressed, but not completely functional, as its intracellular domain is truncated.
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Coloboma , Insuficiência Renal , Feminino , Humanos , Pessoa de Meia-Idade , Coloboma/diagnóstico , Coloboma/genética , Protocaderinas , Caderinas/genéticaRESUMO
Purpose: To describe a group of patients with retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging. Methods: A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls. Results: Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone-rod dystrophy, and had pathogenic RPGR variants located toward the 3'-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance. Conclusions: RPGR-related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone-rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR-related cone or cone-rod dystrophy clinical trials.
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Distrofias de Cones e Bastonetes , Doenças Retinianas , Humanos , Masculino , Feminino , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Estudos Retrospectivos , Retina , Células Fotorreceptoras Retinianas Cones , Proteínas do Olho/genéticaRESUMO
Splice variants are known to cause diseases by utilizing alternative splice sites, potentially resulting in protein truncation or mRNA degradation by nonsense-mediated decay. Splice variants are verified when altered mature mRNA sequences are identified in RNA analyses or minigene assays. Using a quantitative minigene assay, qMini, we uncovered a previously overlooked class of disease-associated splice variants that did not alter mRNA sequence but decreased mature mRNA level, suggesting a potentially new pathogenic mechanism.
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Purpose: To describe the relationships between foveal structure and visual function in a cohort of individuals with foveal hypoplasia (FH) and to estimate FH grade and visual acuity using a deep learning classifier. Design: Retrospective cohort study and experimental study. Participants: A total of 201 patients with FH were evaluated at the National Eye Institute from 2004 to 2018. Methods: Structural components of foveal OCT scans and corresponding clinical data were analyzed to assess their contributions to visual acuity. To automate FH scoring and visual acuity correlations, we evaluated the following 3 inputs for training a neural network predictor: (1) OCT scans, (2) OCT scans and metadata, and (3) real OCT scans and fake OCT scans created from a generative adversarial network. Main Outcome Measures: The relationships between visual acuity outcomes and determinants, such as foveal morphology, nystagmus, and refractive error. Results: The mean subject age was 24.4 years (range, 1-73 years; standard deviation = 18.25 years) at the time of OCT imaging. The mean best-corrected visual acuity (n = 398 eyes) was equivalent to a logarithm of the minimal angle of resolution (LogMAR) value of 0.75 (Snellen 20/115). Spherical equivalent refractive error (SER) ranged from -20.25 diopters (D) to +13.63 D with a median of +0.50 D. The presence of nystagmus and a high-LogMAR value showed a statistically significant relationship (P < 0.0001). The participants whose SER values were farther from plano demonstrated higher LogMAR values (n = 382 eyes). The proportion of patients with nystagmus increased with a higher FH grade. Variability in SER with grade 4 (range, -20.25 D to +13.00 D) compared with grade 1 (range, -8.88 D to +8.50 D) was statistically significant (P < 0.0001). Our neural network predictors reliably estimated the FH grading and visual acuity (correlation to true value > 0.85 and > 0.70, respectively) for a test cohort of 37 individuals (98 OCT scans). Training the predictor on real OCT scans with metadata and fake OCT scans improved the accuracy over the model trained on real OCT scans alone. Conclusions: Nystagmus and foveal anatomy impact visual outcomes in patients with FH, and computational algorithms reliably estimate FH grading and visual acuity.
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BACKGROUND: Uveal colobomata are eye defects that result from failure of the optic fissure of the neuroectoderm-derived optic cup to close between weeks 5-7 of fetal life. Mutations in YAP1 have previously been linked to uveal coloboma. We present the clinical features and genetic basis of a one-year-old male with bilateral uveal colobomata. MATERIALS AND METHODS: Clinical features were gathered from an age-appropriate evaluation and retrospectively from clinical records. DNA samples were collected from the proband, his uncle (who also had coloboma), both parents, and one sibling. Whole-genome sequencing of the coding regions and intron-exon boundaries confirmed a mutation in the proband. These genetic findings were verified using the Sanger method of DNA sequencing. RESULTS: The proband is a male with congenital bilateral colobomata (iris/retina/nerve), reduced vision, nystagmus with null point, bilateral microcornea, right microphthalmia, possible mild right hemifacial microsomia, a tubular nose, possible spina bifida occulta, and astigmatism. Whole-genome sequencing confirmed a heterozygous YAP1 frameshift mutation NM_001130145.3:c.178dupG p.(Asp60GlyfsTer52) in the proband. This mutation was absent in all other tested family members. CONCLUSIONS: We report a de novo mutation in YAP1 that likely results in nonsense-mediated decay. Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband. Further insight into YAP1 mutations may have implications in the prevention/treatment of uveal coloboma and other syndromic disorders.
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Coloboma , Microftalmia , Coloboma/complicações , Coloboma/genética , Mutação da Fase de Leitura , Humanos , Lactente , Masculino , Microftalmia/complicações , Microftalmia/genética , Mutação , Linhagem , Estudos Retrospectivos , Proteínas de Sinalização YAPRESUMO
Uveal coloboma is a condition defined by missing ocular tissues and is a significant cause of childhood blindness. It occurs from a failure of the optic fissure to close during embryonic development and may lead to missing parts of the iris, ciliary body, retina, choroid, and optic nerve. Because there is no treatment for coloboma, efforts have focused on prevention. While several genetic causes of coloboma have been identified, little definitive research exists regarding the environmental causes of this condition. We review the current literature on environmental factors associated with coloboma in an effort to guide future research and preventative counseling related to this condition.
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Coloboma , Corioide , Coloboma/genética , Feminino , Humanos , Gravidez , RetinaRESUMO
Importance: Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix. Objective: To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence. Design, Setting, and Participants: This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021. Main Outcomes and Measures: Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection. Results: Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition. Conclusions and Relevance: This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.
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Neovascularização de Coroide , Degeneração Macular , Distrofias Retinianas , Neovascularização de Coroide/genética , Humanos , Linhagem , Sinais Direcionadores de Proteínas/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismoRESUMO
The retinal dystrophy phenotype associated with CDHR1 retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal dystrophy cohort (10 patients) attributed to autosomal recessive CDHR1 and report novel variants in populations not previously identified with CDHR1-related retinopathy. Seven patients had evaluations covering at least a three-year period. The mean age of individuals at first symptoms was 36 ± 8.5 years (range 5-45 years). Visual acuity at the last visit ranged from 20/20 to 20/2000 (mean LogMAR 0.8 or 20/125). Three clinical subgroups were identified: rod-cone dystrophy (RCD), cone-rod dystrophy (CRD), and maculopathy. Extinguished scotopic electroretinography responses were noted in the RCD patients. Macular involvement was noted in all patients and documented on color fundus photography, fundus autofluorescence, and optical coherence tomography. Notable asymmetry of the degree of macular atrophy was present in two patients. The possible association between CDHR1 variants and clinical findings was predicted using molecular modeling.
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Proteínas Relacionadas a Caderinas , Distrofias de Cones e Bastonetes , Proteínas do Tecido Nervoso , Distrofias Retinianas , Proteínas Relacionadas a Caderinas/genética , Caderinas/genética , Distrofias de Cones e Bastonetes/genética , Eletrorretinografia , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Distrofias Retinianas/genéticaRESUMO
Purpose: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid. Methods: Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT. Results: Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina-like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure. Conclusions: These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure.
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Coloboma , Neuropeptídeos , Animais , Humanos , Camundongos , Coloboma/genética , Coloboma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Melaninas/metabolismo , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Peixe-Zebra/genéticaRESUMO
OBJECTIVE: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. DESIGN: Case series. PARTICIPANTS: Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. METHODS: Complete, age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. RESULTS: Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. CONCLUSIONS: These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.
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Anormalidades Múltiplas/etiologia , Anormalidades do Olho/etiologia , Síndromes de Tricotiodistrofia/complicações , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Catarata/congênito , Contagem de Células , Criança , Pré-Escolar , Córnea/anormalidades , Endotélio Corneano/patologia , Anormalidades do Olho/diagnóstico , Feminino , Humanos , Lactente , Degeneração Macular/congênito , Masculino , Microftalmia , Nistagmo Congênito , Transtornos da Visão/congênito , Acuidade Visual/fisiologia , Xeroderma Pigmentoso/complicações , Adulto JovemRESUMO
Purpose: To describe a family with presumed SOX2 gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.Methods: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the SOX2 gene was confirmed in the proband by Sanger sequencing.Results: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic forme fruste uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent de novo heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.Conclusions: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.
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Microftalmia/diagnóstico , Mosaicismo , Fatores de Transcrição SOXB1/genética , Transtornos dos Cromossomos Sexuais/diagnóstico , Adulto , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Microftalmia/genética , Linhagem , Transtornos dos Cromossomos Sexuais/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Kearns-Sayre Syndrome (KSS) is characterized by pigmentary retinopathy, external ophthalmoplegia and heart block. We report on a now 24-year-old male with clinical retinoschisis and molecularly confirmed KSS. MATERIALS AND METHODS: Physical and complete ophthalmic examination, molecular diagnosis. RESULTS: Over nine years of follow-up, the subject manifested progressive signs and symptoms of KSS, including external ophthalmoplegia/strabismus, ptosis, pigmentary retinopathy, corneal edema, Type I diabetes mellitus, gut dysmotility, sensorineural deafness and heart block. At age 21 he was incidentally found to have retinoschisis on optical coherence tomography that remained stable over three years follow-up. Sequencing of the RS1 gene revealed no pathogenic variants, effectively ruling out co-existing X-linked retinoschisis. CONCLUSIONS: These findings suggest retinoschisis may be a rare manifestation of KSS. A trial of a carbonic anhydrase inhibitor was frustrated by coexisting corneal edema associated with the condition.
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Síndrome de Kearns-Sayre/patologia , Retinosquise/patologia , Adulto , Humanos , Síndrome de Kearns-Sayre/complicações , Síndrome de Kearns-Sayre/diagnóstico por imagem , Masculino , Prognóstico , Retinosquise/complicações , Retinosquise/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adulto JovemRESUMO
We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals.
Assuntos
Encéfalo/anormalidades , Complicações do Diabetes/genética , Proteínas do Olho/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Doenças do Recém-Nascido/genética , Microftalmia/complicações , Mutação/genética , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Microftalmia/genética , Fator de Transcrição PAX6 , LinhagemRESUMO
PURPOSE: To describe the motivations, expectations, and other factors men with X-linked retinoschisis (XLRS) consider when making decisions to participate in an early phase ocular gene therapy clinical trial. DESIGN: Qualitative interview study. METHODS: Men with XLRS who were considering participation in a phase I/IIa ocular gene therapy clinical trial at the National Eye Institute were eligible for this study. Trial participants (n = 9) were interviewed prior to receiving the gene transfer and then at 3 and 12 months later. Trial participation decliners (n = 2) were interviewed at an initial visit and 12 months later. Those screened for the trial and found ineligible (n = 2) were interviewed at an initial visit only. Interviews were transcribed, coded, and analyzed thematically. RESULTS: Interview participants described decision making factors as risk-benefit assessments, personal intuition, trust in the study team, and religious faith. Altruism and the potential for therapeutic benefit were the main motives for trial participation, whereas the uncertainty of risks and benefits was the reason 2 men declined participation. Although most participants hoped for direct benefit, no one expected to benefit. Almost all interview participants considered their decision straightforward and were satisfied with their decision when interviewed over time. Meaningful relationships with the study team and perceived secondary benefits to participation contributed to positive trial experiences. CONCLUSIONS: Engaging prospective research participants in a discussion about their hopes, expectations, and personal factors provides a more complete understanding of patient decision making and may help support informed choices to participate in clinical trials for XLRS.