RESUMO
Objective: To explore the clinical phenotypes and pathogenic gene variation characteristics of three Chinese Han ethnic families affected by Nance-Horan syndrome, a rare X-linked genetic disorder. Methods: A pedigree investigation study was conducted at the First Affiliated Hospital of Zhengzhou University, collecting clinical data from three Chinese Han families with Nance-Horan syndrome between February 2009 and September 2018. Detailed family histories, comprehensive ophthalmological and systemic examinations were documented. Pedigree charts were created, and genetic inheritance patterns were analyzed to preliminarily diagnose the probands and other affected individuals. Genomic DNA was extracted from peripheral blood samples of family members, and next-generation sequencing was used to screen for target gene variations, which were confirmed by Sanger sequencing. Pathogenicity of the genetic variants and their impact on three-dimensional protein structure were analyzed using MutationTaster and computer-aided protein modeling. Results: In Family 1, there are 5 patients, including 4 females (aged 42, 37, 9 and 7) and 1 males (aged 12). In Family 2, there are 5 patients, including 3 females (aged 54, 32 and 16) and 2 males (aged 26 and 9). In Family 3, there are 8 patients, including 5 females (aged 69, 42, 37, 35 and 14) and 3 males (aged 10, 7 and 4). All probands in the three families exhibited nuclear cataracts with typical congenital hereditary cataract features, but no noticeable abnormalities in facial appearance or teeth. Next-generation sequencing identified new variation sites in the NHS gene, specifically c.2519_2520del, exon3del, and c.3847C>T. These variations included nonsense mutation p.(Ser840*), exon deletion p.(?), and nonsense mutation p.(Gln1283*). Combined clinical and genetic sequencing results confirmed X-linked Nance-Horan syndrome in all three families. Bioinformatics analysis indicated these variation sites were pathogenic and resulted in abnormal three-dimensional protein structures, likely being the main cause of Nance-Horan syndrome. Conclusion: The majority of patients from the three Nance-Horan syndrome families studied were affected by congenital hereditary cataracts characterized by nuclear opacities.The NHS gene variations c.2519_2520del, exon3del, and c.3847C>T are newly identified pathogenic sites in Nance-Horan syndrome, reported for the first time across three different families.
Assuntos
Catarata , Mutação , Linhagem , Humanos , Masculino , Feminino , Catarata/genética , Catarata/congênito , Adulto , Pessoa de Meia-Idade , Doenças Genéticas Ligadas ao Cromossomo X/genética , Fenótipo , Povo Asiático/genética , Anormalidades Dentárias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Oftalmopatias Hereditárias/genética , Criança , China , Proteínas de MembranaRESUMO
Purpose: Hereditary eye diseases (HEDs) are individually rare but affect millions globally. The era of molecular genetics has ushered major advances in the study of these disorders; however, the inclusivity and population diversity of this research is unknown. Questions on the accuracy and applicability of these findings in diverse populations, especially African American patients, came up consistently during counselling sessions. This also raised the possibility of missed opportunities for broader understanding of these rare diseases. We conducted a literature review to measure the representation of African Americans in genomic research surrounding nine HEDs. Methods: A detailed literature search using a predetermined set of search terms for each of nine HED categories was performed across PubMed, Embase, Web of Science, and Scopus focusing on studies published between Jan 1990 and July 2021. Predetermined inclusion criteria were applied to filter the sources. Results: We identified 46 studies clearly reporting HED characterization in African Americans. Analysis of these inclusive studies revealed unique findings demonstrating the known usefulness of including diverse cohorts in genomics research. Conclusions: HED characterization in diverse participants, specifically African Americans, is identified as a knowledge gap area. Genomic research is more applicable to patients when conducted in populations that share their ancestral background. Greater inclusion of African Americans in ophthalmic genetics research is a scientific imperative and a needed step in the pursuit of the best possible patient care for populations of all ancestries. Translational Relevance: This work reveals gaps in genomic research in African Americans with HEDs.
Assuntos
Negro ou Afro-Americano , Oftalmopatias Hereditárias , Humanos , Negro ou Afro-Americano/genética , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/etnologia , Genômica/métodosRESUMO
Development of the anterior segment of the eye requires reciprocal sequential interactions between the arising tissues, facilitated by numerous genetic factors. Disruption of any of these processes results in congenital anomalies in the affected tissue(s) leading to anterior segment disorders (ASD) including aniridia, Axenfeld-Rieger anomaly, congenital corneal opacities (Peters anomaly, cornea plana, congenital primary aphakia), and primary congenital glaucoma. Current understanding of the genetic factors involved in ASD remains incomplete, with approximately 50% overall receiving a genetic diagnosis. While some genes are strongly associated with a specific clinical diagnosis, the majority of known factors are linked with highly variable phenotypic presentations, with pathogenic variants in FOXC1, CYP1B1, and PITX2 associated with the broadest spectrum of ASD conditions. This review discusses typical clinical presentations including associated systemic features of various forms of ASD; the latest functional data and genotype-phenotype correlations related to 25 ASD factors including newly identified genes; promising novel candidates; and current and emerging treatments for these complex conditions. Recent developments of interest in the genetics of ASD include identification of phenotypic expansions for several factors, discovery of multiple modes of inheritance for some genes, and novel mechanisms including a growing number of non-coding variants and alleles affecting specific domains/residues and requiring further studies.
Assuntos
Segmento Anterior do Olho , Anormalidades do Olho , Estudos de Associação Genética , Humanos , Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/fisiopatologia , Fenótipo , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/fisiopatologiaRESUMO
Importance: Previous studies have identified familial exudative vitreoretinonpathy (FEVR) in patients with CTNNB1 syndrome based on severe congenital ocular phenotypes. However, ophthalmoscopy may not be sufficient to detect vision-threatening vitreoretinopathy in all patients. Objective: To report a consecutive retrospective case series of 11 patients with CTNNB1 variants who had previously unremarkable ophthalmoscopic examination results and to describe their detailed ophthalmic phenotypes. Design, Setting, and Participants: This retrospective case series was conducted at the Children's Hospital of Philadelphia from October 2022 to November 2023 among patients with identified variants in CTNNB1 and previously documented normal results in office retinal examinations. These consecutive patients subsequently underwent an examination under anesthesia with fluorescein angiography. Detailed genotype information was analyzed for all patients, and each variant was mapped on the CTNNB1 gene to observe any associations with severity of vitreoretinopathy. Main Outcomes and Measures: Number of patients with vitreoretinopathy and number requiring treatment for vitreoretinopathy. Results: The mean (SD) age at the time of CTNNB1 syndrome diagnosis was 2 (1) years, and the mean (SD) age at examination was 6 (3) years for the 11 total patients. A total of 9 patients had a diagnosis of strabismus, and 5 patients had undergone strabismus surgery. FEVR was present in 5 of 11 patients and in 9 eyes. The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment. Detailed genotype analysis of the patients found no clearly delineated high-risk loci in CTNNB1 in association with high severity of FEVR. Conclusions and Relevance: In this case series study, nearly all patients with CTNNB1 syndrome required ophthalmic care for refractive error and strabismus, and a subset also required treatment for FEVR. These findings support consideration of ultra-widefield fluorescein angiography among individuals with CTNNB1 syndrome when feasible, including the use of sedation if such an assessment is not possible in the office setting.
Assuntos
Vitreorretinopatias Exsudativas Familiares , Angiofluoresceinografia , beta Catenina , Humanos , beta Catenina/genética , Masculino , Estudos Retrospectivos , Feminino , Pré-Escolar , Criança , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Angiofluoresceinografia/métodos , Lactente , Oftalmoscopia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Fenótipo , Acuidade Visual/fisiologia , MutaçãoRESUMO
Purpose: This study aims to evaluate the genetic and phenotypic characteristics and elucidate the genotype-phenotype correlations of a large Chinese cohort with PAX6-related disorders. Methods: Variants detected with exome sequencing were filtered through multistep bioinformatic and co-segregation analyses, and validated by Sanger sequencing. The related clinical data were collected, and cluster analysis and statistical analysis of the PAX6-related phenotypes across different variant groups were carried out. Parental mosaicism was investigated using cloning analysis and Droplet digital PCR. Results: A total of 119 pathogenic or likely pathogenic PAX6 variants, including 74 truncation, 31 missense, and 14 others, were identified in 228 patients from 164 unrelated families. The most common phenotypes were foveal hypoplasia (97.8%), nystagmus (92.6%), aniridia (76.7%), cataract (36.8%), and iris hypoplasia (22.4%). Mosaicism ranging from 13.9% to 18.8% was identified in 3 unrelated patients' parents with relatively mild phenotypes. Missense variants in the linker region of the paired domain were associated with high myopia, whereas truncation variants in the homeodomain and proline-serine-threonine-rich domain were associated with hyperopia. Similarly, the degree of iris defects, visual acuity, and associated ocular comorbidity varied among the different types and locations of PAX6 variants. Conclusions: Our data indicate that foveal hypoplasia but not aniridia is the most common sign of PAX6-related disorders, contributing to subtle iris changes that might easily be overlooked in clinical practice. Recognition of mosaicism in atypical cases or parents with very mild phenotypes is important in genetic counseling as their offspring are at increased risk of typical aniridia. Recognition of the genotype-phenotype relationship emphasizes involvement of PAX6 regulation in shaping complex ocular phenotypes.
Assuntos
Estudos de Associação Genética , Fator de Transcrição PAX6 , Linhagem , Fenótipo , Humanos , Fator de Transcrição PAX6/genética , Masculino , Feminino , Adulto , Criança , China/epidemiologia , Pré-Escolar , Adolescente , Povo Asiático/genética , Pessoa de Meia-Idade , Adulto Jovem , Mutação , Sequenciamento do Exoma , Genótipo , Análise Mutacional de DNA , Oftalmopatias Hereditárias/genética , População do Leste AsiáticoRESUMO
Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes.
Assuntos
Cílios , Anormalidades do Olho , Oftalmopatias Hereditárias , Fatores de Transcrição Forkhead , Fenótipo , Transdução de Sinais , Cílios/metabolismo , Cílios/patologia , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Humanos , Animais , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/metabolismo , Camundongos , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Ciliopatias/genética , Ciliopatias/metabolismo , Ciliopatias/patologia , Feminino , Masculino , Proteína Gli2 com Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de Zinco/genética , MutaçãoRESUMO
RATIONALE: Autosomal recessive bestrophinopathy (ARB) is a subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene, which affect the retinal pigment epithelium (RPE). Studying RPE abnormalities through imaging is essential for understanding ARB. This case series involved the use of multimodal imaging techniques, namely autofluorescence (AF) imaging at 488 nm [short-wavelength AF] and 785 nm [near-infrared AF (NIR-AF)] and polarization-sensitive optical coherence tomography (PS-OCT), to investigate RPE changes in 2 siblings with ARB. PATIENT CONCERNS: Two Japanese siblings (Case 1: male, followed for 20-23 years; Case 2: female, followed for 13-17 years) carried compound heterozygous mutations of the BEST1 gene. DIAGNOSIS: Both siblings were diagnosed with ARB. INTERVENTIONS AND OUTCOMES: Multimodal imaging techniques were used to evaluate RPE changes. Both siblings had funduscopic changes similar to those seen in the vitelliruptive stage of Best vitelliform macular dystrophy during the follow-up period. NIR-AF imaging showed hypo-AF of the entire macular lesion in both cases, and this hypo-AF remained stable over time. PS-OCT confirmed reduced RPE melanin content in these hypo-AF areas. Additionally, hyper-NIR-AF dots were observed within hypo-NIR-AF areas. Concomitant identification of focally thickened RPE melanin on PS-OCT imaging and hyper-AF on short-wavelength AF imaging at the sites containing hyper-NIR-AF dots indicated that the hyper-NIR-AF dots had originated from either stacked RPE cells or RPE dysmorphia. LESSONS: We confirmed RPE abnormalities in ARB, including diffuse RPE melanin damage in the macula alongside evidence of RPE activity-related changes. This case series demonstrates that multimodal imaging, particularly NIR-AF and PS-OCT, provides detailed insights into RPE alterations in ARB.
Assuntos
Bestrofinas , Oftalmopatias Hereditárias , Imagem Multimodal , Doenças Retinianas , Epitélio Pigmentado da Retina , Tomografia de Coerência Óptica , Humanos , Imagem Multimodal/métodos , Masculino , Feminino , Tomografia de Coerência Óptica/métodos , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico por imagem , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico por imagem , Epitélio Pigmentado da Retina/diagnóstico por imagem , Epitélio Pigmentado da Retina/patologia , Bestrofinas/genética , Adulto Jovem , Imagem Óptica/métodos , Adolescente , IrmãosRESUMO
BACKGROUND: This case report explores the relationship between genetics and phenotypic variability in autosomal dominant vitreoretinochoroidopathy (ADVIRC). The study focuses on a case presenting a novel mutation in the BEST1 gene and its phenotype in the case's relatives, shedding light on the structural and functional intricacies underlying this rare ophthalmologic disorder. CASE PRESENTATION: A 33-year-old female presented for consultation with a history of bilateral retinal damage accompanied by a complaint of decreased visual acuity, progressive visual field deficit, and night blindness over the past year. Ophthalmic examination revealed a distinctive phenotype, including fibrillar vitreous, pigmented cells, and atrophic hyperpigmented retina in the periphery which was suggestive of a diagnosis of ADVIRC. Genetic testing revealed a heterozygous c.1101-1 G>T variant in BEST1, a novel splice site mutation. Functional analysis confirmed its impact on pre-mRNA splicing, resulting in an in-frame deletion (p(Ser367_Asn579del)). Family investigation revealed varying degrees of ophthalmologic impairment in the patient's mother and half-sister, both carrying the same mutation. CONCLUSIONS: This case report provides the first clinical description of the c.1101-1 G>T mutation in the BEST1 gene associated with ADVIRC. The presence of intrafamilial variability, as evidenced by the differing clinical features observed in the index case and her half-sister, suggests the potential involvement of mechanisms influencing phenotype expression.Abbreviation: ADVIRC : autosomal dominant vitreoretinochoroidopathy; RNA : ribonucleic acid; RPE : retinal pigment epithelium.
Assuntos
Bestrofinas , Canais de Cloreto , Doenças da Coroide , Oftalmopatias Hereditárias , Proteínas do Olho , Linhagem , Fenótipo , Acuidade Visual , Humanos , Feminino , Adulto , Bestrofinas/genética , Doenças da Coroide/genética , Doenças da Coroide/diagnóstico , Proteínas do Olho/genética , Acuidade Visual/fisiologia , Canais de Cloreto/genética , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Doenças Retinianas/patologia , Genes Dominantes , Mutação , Tomografia de Coerência Óptica , Campos Visuais/fisiologia , Angiofluoresceinografia , Degeneração RetinianaRESUMO
Objective: To evaluate the application of whole exome sequencing (WES) in the diagnosis of hereditary eye diseases. Methods: A total of 24 patients who came to the Obstetrics and Gynecology Hospital of Fudan University for reproductive genetic counseling from December 2020 to December 2023 with the main complaint of congenital eye disorders were included in this study. All cases had no known infections or exposure to known teratogenic drugs, karyotype and chromosome microarray analysis (CMA) abnormalities. Genomic DNA was extracted from the peripheral blood of the probands and their family members and tested for WES. Among them, three individual WES and 21 Trio WES were performed. Potential pathogenic sites were screened and analyzed by Sanger sequencing. For RPGRIP1:c.1611+26G>A site, minigene vector was constructed and RT-qPCR was performed to detect the effect of mRNA splicing. Results: A total of 24 families were collected in this study, of which 20 yielded positive results, achieving a diagnosis rate of 83.3% (20/24). The results involved 21 genes and identified 30 distinct variants, 19 of which were new variants reported. Prenatal diagnostic analysis of family 3 revealed that the fetus carried a c.6970G>T heterozygous nonsense mutation in the PRPF8 gene. The results of RT-PCR with the minigene vector at the non-classical splice site in family 24 indicated that the transcription product of the mutant plasmid was partially retained 104 bp in intron 12, resulting in a p.Glu538Valfs*12 alteration of the protein. Conclusions: The high detection rate of WES in the diagnosis of hereditary eye diseases further supports the advantages of its application as an important molecular detection tool for determining the etiology of hereditary eye diseases.
Assuntos
Sequenciamento do Exoma , Oftalmopatias Hereditárias , Humanos , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Feminino , Diagnóstico Pré-Natal/métodos , Mutação , LinhagemRESUMO
PURPOSE: To provide a genotype and phenotype characterization of the BEST1 mutation in Chinese patients with autosomal recessive bestrophinopathy (ARB) through multimodal imaging and next-generation sequencing (NGS). METHODS: Seventeen patients from 17 unrelated families of Chinese origin with ARB were included in a retrospective cohort study. Phenotypic characteristics, including anterior segment features, were assessed by multimodal imaging. Multigene panel testing, involving 586 ophthalmic disease-associated genes, and Sanger sequencing were performed to identify disease-causing variants. RESULTS: Among 17 ARB patients, the mean follow-up was 15.65 months and average onset age was 30.53 years (range: 9-68). Best corrected visual acuity ranged from light perception to 0.8. EOG recordings showed a typically decreased Arden ratio in 12 patients, and a normal or slightly decreased Arden ratio in two patients. Anterior features included shallow anterior chambers (16/17), ciliary pronation (16/17), iris bombe (13/17), iridoschisis (2/17), iris plateau (1/17), narrow angles (16/17) and reduced axial lengths (16/17). Sixteen patients had multiple bilateral small, round, yellow vitelliform deposits distributed throughout the posterior pole, surrounding the optic disc. Initial diagnoses included angle-closure glaucoma (four patients), Best disease (three patients), and central serous chorioretinopathy secondary to choroidal neovascularization (CNV) (one patient), with the remainder diagnosed with ARB. Fourteen patients underwent preventive laser peripheral iridotomy, four of whom also received combined trabeculectomy and iridotomy in both eyes for uncontrolled intraocular pressure. One patient received intravitreal conbercept for CNV. Overall, 15 distinct disease-causing variants of BEST1 were identified, with 14 (82.35%) patients having missense mutations. Common mutations included p. Arg255-256 and p. Ala195Val (both 23.68%), with the most frequent sites in exons 7 and 5. CONCLUSIONS: This study provides a comprehensive characterization of anterior segment and genetic features in ARB, with a wide array of morphological abnormalities. Findings are relevant for refining clinical practices and genetic counseling and advancing pathogenesis research.
Assuntos
Bestrofinas , Oftalmopatias Hereditárias , Acuidade Visual , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Bestrofinas/genética , China/epidemiologia , Análise Mutacional de DNA , População do Leste Asiático , Eletroculografia , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Seguimentos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Imagem Multimodal , Mutação , Linhagem , Fenótipo , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
INTRODUCTION: Familial Exudative Vitreoretinopathy (FEVR) is a heritable retinal vascular disease characterized by incomplete vascularization of the peripheral retina resulting in ischemia. Fifty percent of FEVR cases 10 are due to known pathogenic genetic variants, and disease phenotype can vary greatly. FEVR is a clinical diagnosis, however, genetic testing can play a key role in screening for FEVR in genetically susceptible populations, thus leading to early treatment and improved patient outcomes. CASE: A 2-year-old male with no known past ocular or medical history was diagnosed with FEVR upon examination under anesthesia and multimodal retinal imaging. Genetic testing identified a Jagged 1 (JAG1) variant of uncertain significance, 15 which has been linked to FEVR in recent studies. Despite close follow-up and treatment, the patient experienced a funnel retinal detachment in the right eye approximately one year after diagnosis. DISCUSSION: This case in conjunction with recent literature suggests that JAG1 variants are likely associated with FEVR. Further investigations are necessary to identify the frequency of JAG1 variants among patients with FEVR. Robust understanding of FEVR's heterogenous genetic profile will lead to improved treatment modalities 20 and patient outcomes.
Assuntos
Oftalmopatias Hereditárias , Vitreorretinopatias Exsudativas Familiares , Testes Genéticos , Proteína Jagged-1 , Humanos , Proteína Jagged-1/genética , Masculino , Vitreorretinopatias Exsudativas Familiares/genética , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Pré-Escolar , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Doenças Retinianas/genética , Doenças Retinianas/diagnósticoAssuntos
Vitreorretinopatias Exsudativas Familiares , Genótipo , Encaminhamento e Consulta , Doenças Retinianas , Humanos , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Masculino , Feminino , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Mutação , Linhagem , Angiofluoresceinografia/métodos , Análise Mutacional de DNA , DNA/genéticaRESUMO
BACKGROUND: The clinical approach to inherited eye diseases has evolved due to advances in genetic testing methods and treatment opportunities. However, no data are available on the current practices of ophthalmologists in countries, such as Turkey, with higher rates of consanguinity and inherited eye diseases. The aim of this study was to evaluate the current practices, knowledge, and needs of ophthalmologists in Turkey regarding inherited eye diseases. METHODS: A 29-item self-administered survey with a branching algorithm was developed through Google Forms. The survey link was sent to 2983 ophthalmologists in Turkey. The survey assessed respondents' occupational characteristics, current practices, knowledge about available diagnostic and therapeutic options, and opinions on improving continuing education and healthcare services. RESULTS: Responses from 414 ophthalmologists (20.8%) were analyzed. The responses suggested that ophthalmologists mainly collaborate with medical geneticists in respect of inherited eye diseases. The majority of ophthalmologists reported a lack of knowledge about genetic diagnostic tests, and approximately 90% of the ophthalmologists thought training after residency was inadequate for inherited eye diseases. CONCLUSION: This is the most extensive survey exploring ophthalmologists' practice patterns and needs in a setting without specialists or specialized centers in ophthalmic genetics. The results emphasize the need for continued education on updated approaches to inherited eye diseases.
Assuntos
Oftalmopatias Hereditárias , Avaliação das Necessidades , Oftalmologistas , Humanos , Oftalmologistas/estatística & dados numéricos , Turquia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/epidemiologia , Inquéritos e Questionários , Feminino , Masculino , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Testes Genéticos/estatística & dados numéricos , Pessoa de Meia-Idade , Conhecimentos, Atitudes e Prática em Saúde , OftalmologiaRESUMO
Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the disease, it is difficult to have a specific diagnosis without molecular testing. To date, over 340 genes and loci have been associated with IRDs. We present the molecular finding of 191 individuals with IRD, analyzed by targeted next-generation sequencing (NGS). For 67 of them, we performed a family segregation study, considering a total of 126 relatives. A total of 359 variants were identified, 44 of which were novel. Genetic diagnostic yield was 41%. However, after stratifying the patients according to their clinical suspicion, diagnostic yield was higher for well-characterized diseases such as Stargardt disease (STGD), at 65%, and for congenital stationary night blindness 2 (CSNB2), at 64%. Diagnostic yield was higher in the patient group where family segregation analysis was possible (68%) and it was higher in younger (55%) than in older patients (33%). The results of this analysis demonstrated that targeted NGS is an effective method for establishing a molecular genetic diagnosis of IRDs. Furthermore, this study underlines the importance of segregation studies to understand the role of genetic variants with unknow pathogenic role.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Distrofias Retinianas , Doença de Stargardt , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Adulto , Doença de Stargardt/genética , Linhagem , Criança , Pessoa de Meia-Idade , Cegueira Noturna/genética , Oftalmopatias Hereditárias/genética , Adolescente , Mutação , Degeneração Macular/genética , Miopia/genética , Pré-Escolar , Fenótipo , Adulto Jovem , Idoso , Doenças Genéticas Ligadas ao Cromossomo XRESUMO
PURPOSE: This report aims to delineate distinct phenotypes of Familial Exudative Vitreoretinopathy (FEVR) observed in a mother and her daughter, both harboring a novel LRP5 pathogenic variation. METHODS: The investigation involves a retrospective review of medical records accompanied by multimodal imaging. Molecular characterization was performed using whole exon sequencing, and the pathogenic variant was subsequently confirmed through Sanger sequencing. RESULT: A 6-year-old girl diagnosed with anisometropic amblyopia exhibited macular dragging and peripheral avascular retina in her right eye. Whole exon sequencing identified a previously unreported heterozygous missense LRP5 pathogenic variation, Glu528Lys. Simultaneously, her 43-year-old mother also carried the same mutation, manifesting peripheral exudations, avascular areas, and multiple microaneurysms. Notably, both cases presented distinctive phenotypes of FEVR. CONCLUSION: Our findings underscore the diversity in clinical presentations associated with FEVR, emphasizing the pivotal role of genetic evaluation. Despite variations in severity between the eyes of the same patient, it is crucial to remain vigilant for potential progression to a pathological status in the seemingly normal eye. Additionally, this study contributes to expanding the genetic spectrum of FEVR.
Assuntos
Vitreorretinopatias Exsudativas Familiares , Angiofluoresceinografia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Linhagem , Fenótipo , Tomografia de Coerência Óptica , Humanos , Feminino , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Vitreorretinopatias Exsudativas Familiares/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Adulto , Criança , Estudos Retrospectivos , Análise Mutacional de DNA , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Acuidade Visual/fisiologia , Mutação de Sentido Incorreto , Mães , Imagem Multimodal , DNA/genética , Éxons/genéticaRESUMO
This report describes a unique case of a Coats-like presentation of familial exudative vitreoretinopathy in an 11-year-old girl. The patient was originally referred for evaluation of presumed Coats disease and presented with telangiectatic vessels, perivascular exudates, diffuse peripheral exudation, and intraretinal hemorrhages. Clinical and angiographical findings were consistent with familial exudative vitreoretinopathy, while genetic testing identified variants of uncertain significance in two associated genes, LRP5 and ZNF408. In silico analysis predicts the LRP5 variant to be pathogenic. Retinal vasculopathies often have phenotypic overlap, warranting angiographic examination of both eyes and genetic testing to uncover the correct diagnosis and guide proper treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:462-466.].
Assuntos
Vitreorretinopatias Exsudativas Familiares , Angiofluoresceinografia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Humanos , Feminino , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Criança , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Angiofluoresceinografia/métodos , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/genética , Tomografia de Coerência Óptica/métodos , Fundo de Olho , Mutação , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Linhagem , Proteínas de Ligação a DNA , Fatores de TranscriçãoRESUMO
Inherited retinal dystrophies (IRDs) are characterized by photoreceptor dysfunction or degeneration. Clinical and phenotypic overlap between IRDs makes the genetic diagnosis very challenging and comprehensive genomic approaches for accurate diagnosis are frequently required. While there are previous studies on IRDs in Pakistan, causative genes and variants are still unknown for a significant portion of patients. Therefore, there is a need to expand the knowledge of the genetic spectrum of IRDs in Pakistan. Here, we recruited 52 affected and 53 normal individuals from 15 consanguineous Pakistani families presenting non-syndromic and syndromic forms of IRDs. We employed single molecule Molecular Inversion Probes (smMIPs) based panel sequencing and whole genome sequencing to identify the probable disease-causing variants in these families. Using this approach, we obtained a 93% genetic solve rate and identified 16 (likely) causative variants in 14 families, of which seven novel variants were identified in ATOH7, COL18A1, MERTK, NDP, PROM1, PRPF8 and USH2A while nine recurrent variants were identified in CNGA3, CNGB1, HGSNAT, NMNAT1, SIX6 and TULP1. The novel MERTK variant and one recurrent TULP1 variant explained the intra-familial locus heterogeneity in one of the screened families while two recurrent CNGA3 variants explained compound heterozygosity in another family. The identification of variants in known disease-associated genes emphasizes the utilization of time and cost-effective screening approaches for rapid diagnosis. The timely genetic diagnosis will not only identify any associated systemic issues in case of syndromic IRDs, but will also aid in the acceleration of personalized medicine for patients affected with IRDs.
Assuntos
Consanguinidade , Sequenciamento de Nucleotídeos em Larga Escala , Linhagem , Humanos , Paquistão , Masculino , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Criança , Mutação , Adulto , Adolescente , Análise Mutacional de DNA , Adulto Jovem , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Pré-Escolar , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Testes Genéticos/métodos , Sequenciamento Completo do GenomaRESUMO
Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.
Assuntos
Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Rodopsina , Animais , Cegueira Noturna/genética , Cegueira Noturna/metabolismo , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Camundongos , Rodopsina/genética , Rodopsina/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Miopia/genética , Miopia/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Escuridão , Transducina/genética , Transducina/metabolismo , Técnicas de Introdução de Genes , Modelos Animais de DoençasRESUMO
Importance: Data regarding the prevalence of various inherited retinal diseases (IRDs) are limited and vary across populations; moreover, nationwide prevalence studies may be limited to a specific IRD phenotype, potentially leading to inaccurate prevalence estimations. Therefore, nationwide prevalence data are needed. Objective: To determine the prevalence of 67 IRD phenotypes in the Israeli population. Design, Setting, and Participants: This cohort study collected nationwide data regarding the number of individuals affected with IRD phenotypes assessed in 10 clinical and academic centers in Israel as part of the research activity of the Israeli inherited retinal disease consortium. Data were collected in May 2023 on 9396 individuals residing in Israel who were diagnosed by an ophthalmologist with an IRD using either electroretinography or retinal imaging where included. Individuals with retinal diseases known to have a nonmendelian basis or without a clear genetic basis and those who were reported as deceased at the time of data collection were excluded from this study. Main Outcomes and Measures: Prevalence of 67 IRD phenotypes. Results: Among the 9396 participants in our cohort, the most common IRD in Israel was retinitis pigmentosa with a disease prevalence of approximately 1:2400 individuals, followed by cone-rod dystrophy (approximately 1:14â¯000), Stargardt disease (approximately 1:16â¯000), Usher syndrome (approximately 1:16,000), and congenital stationary night blindness (approximately 1:18â¯000). The prevalence of all IRDs combined was 1:1043 individuals. Conclusions and Relevance: The current study provides large prevalence dataset of 67 IRD phenotypes, some of which are extremely rare, with only a single identified case. This analysis highlights the potential importance of performing additional nationwide prevalence studies to potentially assist with determining the prevalence of IRDs worldwide.
Assuntos
Eletrorretinografia , Doenças Retinianas , Humanos , Israel/epidemiologia , Prevalência , Masculino , Feminino , Adulto , Doenças Retinianas/epidemiologia , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Pessoa de Meia-Idade , Fenótipo , Adolescente , Adulto Jovem , Idoso , Criança , Oftalmopatias Hereditárias/epidemiologia , Oftalmopatias Hereditárias/genética , Pré-EscolarRESUMO
BACKGROUND: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. CASE REPORTS: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. CONCLUSIONS: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR.