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1.
Clin Dysmorphol ; 33(2): 63-68, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38441200

RESUMO

Aniridia is an autosomal dominant condition characterized by the complete or partial absence of the iris, often with additional presentations such as foveal hypoplasia, nystagmus, cataract, glaucoma and other ocular abnormalities. Most cases are caused by heterozygous mutations in the paired box 6 gene (PAX6), which codes for a transcription factor that regulates eye development. Four patients from our hospital who presented with ocular phenotypes were recruited for research sequencing with informed consent. Sanger sequencing of PAX6 coding exons or exome sequencing was performed on genomic DNA from venous blood samples. Variants in PAX6 were identified in the four patients. Two variants are recurrent single-nucleotide substitutions - one is a substitution found in a patient with bilateral aniridia, whereas the other is a splice variant in a patient with nystagmus and neuroblastoma. The other two variants are novel and found in two patients with isolated aniridia. Both are small duplications that are predicted to lead to premature termination. For the recurrent variants, the comparison of phenotypes for patients with identical variants would shed light on the mechanisms of pathogenesis, and the discovery of two novel variants expands the spectrum of PAX6 mutations.


Assuntos
Aniridia , Catarata , Humanos , Face , Aniridia/genética , Catarata/genética , Éxons , Sudeste Asiático , Fator de Transcrição PAX6/genética
2.
J Med Genet ; 61(3): 250-261, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38050128

RESUMO

BACKGROUND: Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the PAX6 locus. METHODS: Short-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the PAX6 coding region. RESULTS: Likely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the PAX6 locus. Of these 19 families, 1 has a novel heterozygous PAX6 frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of PAX6 5' non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of PAX6, 3 have deletions encompassing critical PAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the PAX6 locus and 2 have complex rearrangements disrupting PAX6. The remaining 3 of 22 families have deletions encompassing FOXC1 (a known cause of atypical aniridia). Seven of the causative variants occurred de novo and one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in PAX6 cis-regulatory elements. CONCLUSION: Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.


Assuntos
Aniridia , Anormalidades do Olho , Humanos , Fator de Transcrição PAX6/genética , Aniridia/genética , Mutação/genética , Anormalidades do Olho/genética , Éxons , Proteínas de Homeodomínio/genética , Proteínas do Olho/genética , Linhagem
3.
Exp Eye Res ; 238: 109746, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38056551

RESUMO

Heterozygous mutation of PAX6 in humans leads to congenital aniridia (OMIM 106210) which is typified by congenital iris and foveal defects, and later onset glaucoma, aniridic keratopathy, and cataract. Mice heterozygous for Pax6 mutations phenocopy many aspects of aniridia including the iris defects, keratopathy and cataract, although Pax6 mutant mice have small lenses, a phenotype which is not typically reported in human aniridia, perhaps due to difficulties in measuring lens diameter during typical ophthalmic examinations as the lens periphery is shielded by the iris. In order to overcome this, records of patients diagnosed with congenital aniridia between April 2015 and May 2021 at the Necker-Enfants Malades Hospital, and genetically confirmed with a disease-causing PAX6 variant, were retrospectively reviewed for those with normal axial length whose iris defects allowed visualization of the lens margins and corneal diameter to allow calculation of a lens/corneal diameter ratio. This value was compared with values obtained from a cohort of patients with Sjödell grade IV oculocutaneous albinism type 1 (OCA1; OMIM 203100) which allowed visualization of the lens periphery via iris transillumination. This analysis revealed that patients with congenital aniridia had a significantly lower lens/corneal ratio when compared to those with albinism, suggesting that humans haploinsufficient for PAX6, like mice, rats, frogs, and zebrafish, exhibit reductions in lens size.


Assuntos
Aniridia , Catarata , Doenças da Córnea , Humanos , Camundongos , Ratos , Animais , Fator de Transcrição PAX6/genética , Fatores de Transcrição Box Pareados/genética , Estudos Retrospectivos , Peixe-Zebra , Aniridia/genética , Aniridia/diagnóstico , Mutação , Catarata/genética , Catarata/congênito , Proteínas de Homeodomínio/genética , Proteínas do Olho/genética
4.
Mov Disord ; 39(1): 141-151, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37964426

RESUMO

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Aniridia , Anidrases Carbônicas , Ataxia Cerebelar , Deficiência Intelectual , Transtornos dos Movimentos , Degenerações Espinocerebelares , Humanos , Ataxia Cerebelar/genética , Mutação de Sentido Incorreto/genética , Transtornos dos Movimentos/complicações , Atrofia , Receptores de Inositol 1,4,5-Trifosfato/química , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética
5.
Exp Eye Res ; 238: 109723, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37979905

RESUMO

Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies.


Assuntos
Aniridia , Microftalmia , Humanos , Camundongos , Animais , Fator de Transcrição PAX6/genética , Fatores de Transcrição Box Pareados/genética , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Microftalmia/genética , Aniridia/genética , Proteínas de Homeodomínio/genética , Proteínas do Olho/genética
6.
Mil Med ; 189(1-2): e443-e447, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37534897

RESUMO

Traumatic aniridia from combat ocular trauma can cause visual disability. A 41-year-old male Army Veteran was referred for evaluation of light sensitivity and glare secondary to subtotal traumatic aniridia of his left eye from an improvised explosive device blast. A custom-made artificial iris prosthesis was implanted in the ciliary sulcus and secured using Gore-Tex sutures. After surgery, the patient reported improvement of his light sensitivity and quality of life. The custom iris prosthesis is a surgical option for visual disability resulting from traumatic aniridia from combat ocular trauma.


Assuntos
Aniridia , Traumatismos Oculares , Masculino , Humanos , Adulto , Implantação de Prótese/métodos , Iris/cirurgia , Iris/lesões , Aniridia/complicações , Aniridia/cirurgia , Fotofobia/complicações , Fotofobia/cirurgia , Qualidade de Vida , Traumatismos Oculares/complicações , Traumatismos Oculares/cirurgia , Próteses e Implantes/efeitos adversos
7.
Int J Mol Sci ; 24(23)2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38069245

RESUMO

Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.


Assuntos
Aniridia , Neoplasias Renais , Síndrome WAGR , Tumor de Wilms , Masculino , Humanos , Lactente , Síndrome WAGR/diagnóstico , Síndrome WAGR/genética , Síndrome WAGR/patologia , Deleção Cromossômica , Aniridia/diagnóstico , Aniridia/genética , Tumor de Wilms/genética , Neoplasias Renais/genética , Cromossomos Humanos Par 11/genética , Inversão Cromossômica
8.
Int J Mol Sci ; 24(21)2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37958513

RESUMO

This study aims to present a clinical case involving the unique co-occurrence of congenital aniridia and Down syndrome in a young girl and to analyze the combined impact of these conditions on the patient's phenotype. The investigation involved comprehensive pediatric and ophthalmological examinations alongside karyotyping and Sanger sequencing of the PAX6 gene. The patient exhibited distinctive features associated with both congenital aniridia and Down syndrome, suggesting a potential exacerbation of their effects. Cytogenetic and molecular genetic analysis revealed the presence of trisomy 21 and a known pathogenic nonsense variant in exon 6 of the PAX6 gene (c.282C>A, p.(Cys94*)) corresponding to the paired domain of the protein. The observation of these two hereditary anomalies offers valuable insights into the molecular pathogenetic mechanisms underlying each condition. Additionally, it provides a basis for a more nuanced prognosis of the complex disease course in this patient. This case underscores the importance of considering interactions between different genetic disorders in clinical assessments and treatment planning.


Assuntos
Aniridia , Síndrome de Down , Feminino , Humanos , Criança , Síndrome de Down/complicações , Fator de Transcrição PAX6/genética , Cromossomos Humanos Par 21/genética , Trissomia , Aniridia/complicações , Aniridia/genética , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Linhagem , Mutação
9.
Genes (Basel) ; 14(11)2023 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-38002984

RESUMO

This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia.


Assuntos
Aniridia , Síndrome WAGR , Humanos , Prevalência , Fator de Transcrição PAX6/genética , Aniridia/epidemiologia , Aniridia/genética , Síndrome WAGR/genética , Deleção Cromossômica
11.
J AAPOS ; 27(6): 357-359, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37742703

RESUMO

Aniridia is an autosomal dominant congenital malformation associated with mutations in the PAX6 gene. It can be associated with deletion in the contiguous WT1 gene, leading to WAGR syndrome, characterized by Wilm tumor, aniridia, genitourinary anomalies, and mental retardation. Persistent fetal vasculature is a developmental malformation caused by incomplete regression of hyaloid vasculature. Most cases of persistent fetal vasculature occur sporadically; however, some inherited forms are described. We report a case of genetically confirmed WAGR associated with congenital cataract and persistent fetal vasculature.


Assuntos
Aniridia , Deficiência Intelectual , Síndrome WAGR , Humanos , Síndrome WAGR/diagnóstico , Síndrome WAGR/genética , Síndrome WAGR/patologia , Deleção Cromossômica , Aniridia/diagnóstico , Aniridia/genética , Aniridia/patologia , Deficiência Intelectual/genética , Mutação
12.
BMC Ophthalmol ; 23(1): 393, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37752489

RESUMO

BACKGROUND: To identify the disease-causing gene in a Chinese family affected with congenital aniridia. METHODS: Patients underwent systematic ophthalmic examinations such as anterior segment photography, fundus photography, optical coherence tomography, and fundus fluorescein angiography. The proband was screened for pathogenic variants by whole exome sequencing (WES) and copy number variant (CNV) analysis. Real-time quantitative PCR (RT-qPCR) was applied to confirm the CNV results. Breakpoints were identified by long-range PCR followed by Sanger sequencing. RESULTS: All seven members of this Chinese family, including four patients and three normal individuals, were recruited for this study. All patients showed bilateral congenital aniridia with nystagmus, except the son of the proband, who presented with bilateral partial coloboma of the iris. A novel heterozygous deletion (chr11:31,139,019-31,655,997) containing the 3' regulatory enhancers of the PAX6 gene was detected in this family. We also reviewed the reported microdeletions downstream of PAX6 in patients with aniridia. CONCLUSIONS: We identified a novel microdeletion, 517 kb in size located about 133 kb downstream of the PAX6 gene, responsible for congenital aniridia in this Chinese family, which expands the spectrum of aniridia-associated mutations in PAX6.


Assuntos
Aniridia , População do Leste Asiático , Fator de Transcrição PAX6 , Humanos , Aniridia/genética , Angiofluoresceinografia , Iris , Fator de Transcrição PAX6/genética , Deleção de Sequência
13.
Orv Hetil ; 164(34): 1342-1349, 2023 Aug 27.
Artigo em Húngaro | MEDLINE | ID: mdl-37634154

RESUMO

INTRODUCTION: Aniridia is a rare congenital panocular disease associated with varying degrees of visual acuity impairment. OBJECTIVE: To assess the experiences of congenital aniridia patients in Hungary, with visual impairment using a questionnaire developed by the ANIRIDIA-NET. PATIENTS AND METHOD: Patients completed the Hungarian version of the 20-item ANIRIDIA-NET questionnaire with our assistance. The questionnaire covered demographic data, the most common complaints caused by the disease, the difficulties caused by low vision in different life situations and the frequency of low vision aids used in daily life. RESULTS: 33 subjects (17 female [51.51%] and 16 male [48.48%]), 16 (48.5%) children and 17 (51.5%) adults completed the questionnaire, with an age of 25.69 ± 17.49 years (5-59 years). Daily photosensitivity was reported by 27 (81.8%), dry eyes by 5 (15.2%), tearing by 4 (12.1%), fluctuating vision by 3 (9.1%), and eye pain by 2 (6.1%) subjects. The majority of respondents said that personal communication with schoolmates (16 [48.5%]) or colleagues at work (11 [33.3%]) never caused difficulties because of their visual impairment. 29 people (87.9%) never needed help with daily routines at home, 24 (72.7%) with getting to school/work and 17 (51.5%) with various activities. 29 people (87.8%) never used low vision aids for communication, 23 (69.7%) for travelling, 20 (60.6%) for participating in social activities, 18 (54.5%) for studying/work. CONCLUSION: Although aniridia is associated with reduced visual acuity, the majority of people with congenital aniridia, especially in childhood, manage to cope with personal communication and various life situations without difficulty, despite their eye complaints. Low vision aids can be an important aid for them as they grow into adulthood and as they age. Orv Hetil. 2023; 164(34): 1342-1349.


Assuntos
Aniridia , Ceratoconjuntivite Seca , Baixa Visão , Adulto , Criança , Humanos , Feminino , Masculino , Adolescente , Adulto Jovem , Hungria , Aniridia/complicações , Comunicação , Doenças Raras
14.
Stem Cells ; 41(12): 1133-1141, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-37632794

RESUMO

Congenital aniridia is caused by heterozygous mutations on the PAX6 gene leading to reduced amount of PAX6 protein (haploinsufficiency), abnormal eye development, and aniridia-associated keratopathy (AAK). This progressive corneal opacification resembles late-onset limbal stem cell (LSC) deficiency, leading to disrupted corneal epithelial renewal. The factors leading to AAK are not known and defects in native LSC differentiation and/or features leading to ocular surface dysfunction like inflammation and loss of innervation could contribute to development of AAK. Here, we produced induced pluripotent stem cells (hiPSC) from 3 AAK patients and examined whether PAX6 haploinsufficiency affects LSC lineage commitment. During LSC differentiation, characterization of the AAK lines showed lowered PAX6 expression as compared to wild type (WT) controls and expression peak of PAX6 during early phase of differentiation was detected only in the WT hiPSC lines. Whether it reflects developmental regulation remains to be studied further. Nevertheless, the AAK-hiPSCs successfully differentiated toward LSC lineage, in line with the presence of LSCs in young patients before cell loss later in life. In addition, patient-specific LSCs showed similar wound healing capacity as WT cells. However, extensive batch-related variation in the LSC marker expression and wound healing efficacy was detected without clear correlation to AAK. As development and maintenance of corneal epithelium involves an interplay between LSCs and their environment, the AAK-hiPSCs generated here can be further used to study the crosstalk between LSCs and limbal niche including, eg, corneal immune cells, stroma cells, and neurons.


Assuntos
Aniridia , Doenças da Córnea , Epitélio Corneano , Células-Tronco Pluripotentes Induzidas , Limbo da Córnea , Humanos , Córnea , Epitélio Corneano/metabolismo , Doenças da Córnea/genética , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Aniridia/genética
15.
Indian J Ophthalmol ; 71(8): 3118, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37530301

RESUMO

Background: Aniridia is defined as missing iris tissue which can be partial, subtotal, or total. Characteristic clinical symptoms include photophobia and decreased visual acuity due to an increased light perception. In addition to this, disturbing cosmetic problems are prevalent. Even after implantation of an intraocular lens, patients often tend to be unsatisfied. Purpose: The answer to this problem lies in the implantation of an aniridic scleral fixation of intraocular lens (SFIOL), which has a central optical axis that acts as the refractive lens and a peripheral rim of a hyperpigmented area that mimics the iris and hence reduces photophobia. The purpose of the video was to demonstrate the use of black diaphragm intraocular lens (BDIOL) implantation, its surgical steps, and its outcomes. Synopsis: We report one such case where a young patient presented with post-traumatic aniridia with subluxated total cataract and spillover vitreous hemorrhage. He was subjected to a vitrectomy, cataract removal, and placement of an aniridic SFIOL with prolene 9-0 using the four-point fixation method. This gave an extremely gratifying outcome and solved both problems, that is, vision and photophobia. Highlight: Before implantation of the SFIOL, the patients had reduced visual acuity from aphakia and intolerable glare from aniridia. In this case-based approach and with relevant example, we tried to provide a solution for tricky scenarios like co-existing traumatic cataract and traumatic aniridia. The patient showed improved visual acuity and marked glare reduction after black diaphragm SFIOL implantation. Video link: https://youtu.be/atl60WetFsM.


Assuntos
Aniridia , Catarata , Traumatismos Oculares , Lentes Intraoculares , Masculino , Humanos , Implante de Lente Intraocular , Fotofobia/diagnóstico , Fotofobia/etiologia , Fotofobia/cirurgia , Iris/cirurgia , Aniridia/complicações , Transtornos da Visão/cirurgia , Traumatismos Oculares/complicações , Catarata/complicações
16.
BMC Med Genomics ; 16(1): 182, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37542296

RESUMO

BACKGROUND: The genotype characteristics and their associated clinical phenotypes in patients with aniridia were analyzed to explore pathogenic variants using whole-exome sequencing. METHODS: One patient with aniridia was enrolled at the Beijing Tongren Hospital. Comprehensive ophthalmic and general examinations were performed on the patient. DNA was extracted from the patient, and whole-exome sequencing was performed to identify the causative variant. The pathogenicity of the variant was predicted using in silico analysis and evaluated according to American College of Medical Genetics and Genomics guidelines. Relationships between genetic variants and clinical features were analyzed. RESULTS: In addition to the classical aniridia phenotype showing complete iris aplasia, foveal hypoplasia, and ectopic lentis, the patient also exhibited spontaneous reattachment rhegmatogenous retinal detachment (SRRRD). Whole-exome sequencing identified a novel heterozygous variant, exon8:c.640_646del:p.R214Pfs*28. CONCLUSIONS: The present study broadens the range of genetic variants described in aniridia and presents an aniridia patient with SRRRD.


Assuntos
Aniridia , Descolamento Retiniano , Humanos , Aniridia/complicações , Aniridia/genética , Aniridia/patologia , População do Leste Asiático , Genótipo , Proteínas de Homeodomínio/genética , Mutação , Fator de Transcrição PAX6/genética , Linhagem
17.
BMC Ophthalmol ; 23(1): 349, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37553561

RESUMO

BACKGROUND: According to previous reports, PAX6-associated foveal hypoplasia (FH) could usually be accompanied by various anterior segment anomalies including variable iris changes. This study aims to exhibit unusual phenotypes of a novel missense variant of PAX6 from a Chinese pedigree. METHODS: Ophthalmic examinations including slit-lamp biomicroscopy, gonioscopy, ophthalmic ultrasound, ultrasonic biomicroscopy, optical coherence tomography, wide-field fundus imaging, and visual field test were performed to evaluate the clinical manifestations. Whole-exome sequencing (WES) and bioinformatics analysis were conducted in eight members from this pedigree to identify the causative mutation. RESULTS: WES revealed a novel heterozygous substitution of PAX6 (NM_000280.5:c.157G > A, p.(Val53Met) (chr11:31823309 C > T, hg19)), which cosegregated with the phenotype of this pedigree. All the three patients (a pair of fraternal twins and their mother) exhibited bilateral FH and anterior segment dysgenesis (ASD) including microcornea, sclerocornea, obvious symmetrical corectopia, iris stromal dysplasia, goniodysgenesis, and abnormal distribution of fundus blood vessels. The girl of the fraternal twins also demonstrated bilateral temporal deviation of lenses and abnormal tissue membrane connecting anterior chamber angle and lens anterior capsule in the right eye. The mother additionally showed apparent cataract bilaterally and cupping of the optic disc in her left eye. CONCLUSION: A novel missense variant in PAX6 gene was detected in a Chinese pedigree demonstrating bilateral FH and ASD. It is really distinctive that the ASD involves almost all parts of the anterior segment, and bilateral symmetrical corectopia is the most perceptible sign. This study expands the phenotypic and genotypic spectrum of PAX6-associated ocular diseases, and facilitates the understanding of the crucial role that PAX6 plays in the development of the eye. Meanwhile, PAX6 could be considered as a candidate pathogenic gene of bilateral symmetrical corectopia.


Assuntos
Aniridia , Proteínas de Homeodomínio , Feminino , Humanos , Fator de Transcrição PAX6/genética , Proteínas de Homeodomínio/genética , Genótipo , Fenótipo , Mutação , Linhagem , Proteínas do Olho/genética , Aniridia/diagnóstico , Aniridia/genética , Aniridia/complicações
18.
Orv Hetil ; 164(27): 1063-1069, 2023 Jul 09.
Artigo em Húngaro | MEDLINE | ID: mdl-37422887

RESUMO

INTRODUCTION: Congenital aniridia is a rare panocular disease that affects almost all eye structures leading in most patients to reduced visual acuity. Ophthalmological signs include aniridia-associated keratopathy, secondary glaucoma, cataract, macular and optic nerve head hypoplasia, nystagmus. Although the term aniridia-associated keratopathy has long been used in the literature, various staging proposals have been described. OBJECTIVE: To analyze aniridia-associated keratopathy stages, using available literature classifications, in patients with aniridia in Hungary. PATIENTS AND METHODS: We examined 65 eyes of 33 patients with congenital aniridia (age: 25.69 ± 17.49 [5-59] years, 17 females [51.51%]). We recorded the corneal status by slit-lamp examination and classified the corneal abnormalities according to the Mackman, Mayer, López-García and Lagali staging. RESULTS: According to Mackman's classification, 8 eyes (12.3%) were in stage 0, 0 eye in stage 1A, 38 eyes (58.46%) in stage 1B and 19 eyes (29.23%) in stage 2. According to Mayer, stage I included 8 eyes (12.3%), stage II 38 eyes (58.46%), stage III 5 eyes (7.7%), stage IV 7 eyes (10.77%) and stage V 7 eyes (10.77%). In López-García's classification, 8 eyes (12.3%) could not be grouped, 20 eyes (30.77%) were in stage 1, 18 eyes (27.7%) in stage 2 and 19 eyes (29.3%) in stage 3. Lagali's classification included 8 eyes (12.3%) in stage 0, 20 eyes (30.77%) in stage 1, 18 eyes (27.7%) in stage 2, 5 eyes (7.7%) in stage 3 and 14 eyes (21.54%) in stage 4. CONCLUSION: We recommend using Lagali's staging scheme for aniridia-associated keratoptahy due to its ease of use, detailed progression assessment, and treatment planning. In stage 1 according to Lagali, blood vessels cross the limbus by up to 1 mm, in stage 2 the central 2-3 mm of the corneal area is spared of blood vessels. When the blood vessels reach the center of the cornea, it is stage 3, followed by opaque, uneven corneal pannus in stage 4. Orv Hetil. 2023; 164(27): 1063-1069.


Assuntos
Aniridia , Catarata , Doenças da Córnea , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Doenças da Córnea/etiologia , Aniridia/complicações , Aniridia/diagnóstico , Córnea , Transtornos da Visão
19.
J AAPOS ; 27(4): 194.e1-194.e6, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37499898

RESUMO

PURPOSE: To report on the incidence, characteristics, and treatment of glaucoma in association with aniridia in a population of Egyptian children. METHODS: A retrospective chart review was conducted of children (<18 years of age) presenting with aniridia between 2007 and 2022. Diagnosis of glaucoma was based on cup:disk ratio (>0.3) and IOP (>16 mm Hg). Success of glaucoma surgery was defined as IOP ≤16 mm Hg and stable or regressing cup:disk ratio. RESULTS: A total of 93 eyes of 47 children were included. The mean patient age at presentation was 41.2 ± 44.7 months. The mean intraocular pressure (IOP), corneal diameter, cup:disk ratio, and axial length on presentation were 16.4 ± 10.3 mm Hg, 11.4 ± 1.3 mm, 0.4 ± 0.3, and 22.43 ± 2.6 mm Hg. Of eyes with IOP and cup:disk ratio data at presentation, 23 (30%) were diagnosed with glaucoma. Fourteen eyes underwent surgery after presentation; follow-up data were available for half the remaining eyes. At the final follow-up, glaucoma was present in 20 eyes (49%). Glaucoma surgery was performed in 17 eyes, with a complete or qualified success rate of 82.4% at final follow-up, with 15 eyes having at least 12 months' follow-up. CONCLUSIONS: In this study cohort, children with aniridia presented at around 3 years of age, with glaucoma at presentation in almost one-third of the cases.


Assuntos
Aniridia , Glaucoma , Trabeculectomia , Humanos , Criança , Pré-Escolar , Estudos Retrospectivos , Egito/epidemiologia , Glaucoma/diagnóstico , Glaucoma/epidemiologia , Glaucoma/cirurgia , Pressão Intraocular , Aniridia/complicações , Aniridia/epidemiologia , Aniridia/cirurgia , Resultado do Tratamento , Seguimentos
20.
Hum Genomics ; 17(1): 45, 2023 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-37269011

RESUMO

BACKGROUND: Haploinsufficiency of the transcription factor PAX6 is the main cause of congenital aniridia, a genetic disorder characterized by iris and foveal hypoplasia. 11p13 microdeletions altering PAX6 or its downstream regulatory region (DRR) are present in about 25% of patients; however, only a few complex rearrangements have been described to date. Here, we performed nanopore-based whole-genome sequencing to assess the presence of cryptic structural variants (SVs) on the only two unsolved "PAX6-negative" cases from a cohort of 110 patients with congenital aniridia after unsuccessfully short-read sequencing approaches. RESULTS: Long-read sequencing (LRS) unveiled balanced chromosomal rearrangements affecting the PAX6 locus at 11p13 in these two patients and allowed nucleotide-level breakpoint analysis. First, we identified a cryptic 4.9 Mb de novo inversion disrupting intron 7 of PAX6, further verified by targeted polymerase chain reaction amplification and sequencing and FISH-based cytogenetic analysis. Furthermore, LRS was decisive in correctly mapping a t(6;11) balanced translocation cytogenetically detected in a second proband with congenital aniridia and considered non-causal 15 years ago. LRS resolved that the breakpoint on chromosome 11 was indeed located at 11p13, disrupting the DNase I hypersensitive site 2 enhancer within the DRR of PAX6, 161 Kb from the causal gene. Patient-derived RNA expression analysis demonstrated PAX6 haploinsufficiency, thus supporting that the 11p13 breakpoint led to a positional effect by cleaving crucial enhancers for PAX6 transactivation. LRS analysis was also critical for mapping the exact breakpoint on chromosome 6 to the highly repetitive centromeric region at 6p11.1. CONCLUSIONS: In both cases, the LRS-based identified SVs have been deemed the hidden pathogenic cause of congenital aniridia. Our study underscores the limitations of traditional short-read sequencing in uncovering pathogenic SVs affecting low-complexity regions of the genome and the value of LRS in providing insight into hidden sources of variation in rare genetic diseases.


Assuntos
Aniridia , Fatores de Transcrição Box Pareados , Humanos , Fatores de Transcrição Box Pareados/genética , Proteínas de Homeodomínio/genética , Proteínas Repressoras/genética , Aniridia/genética , Inversão Cromossômica , Mutação
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