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Journal of Medical Genetics Feb 2024Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and...
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 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 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 locus. Of these 19 families, 1 has a novel heterozygous frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of 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 , 3 have deletions encompassing critical -regulatory elements, 2 have balanced inversions with disruptive breakpoints within the locus and 2 have complex rearrangements disrupting . The remaining 3 of 22 families have deletions encompassing (a known cause of atypical aniridia). Seven of the causative variants occurred and one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in -regulatory elements.
CONCLUSION
Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.
Topics: Humans; PAX6 Transcription Factor; Aniridia; Mutation; Eye Abnormalities; Exons; Homeodomain Proteins; Eye Proteins; Pedigree
PubMed: 38050128
DOI: 10.1136/jmg-2023-109181 -
Journal of Clinical Medicine May 2024: Aniridia-associated keratopathy (AAK) is a potentially vision-threatening pathology in congenital aniridia, for which both the underlying etiopathogenesis and...
: Aniridia-associated keratopathy (AAK) is a potentially vision-threatening pathology in congenital aniridia, for which both the underlying etiopathogenesis and effective treatment remain unclear. :This prospective study was conducted to assess and compare the short-term outcome after superficial keratectomy (SK) alone or in a combination with an amniotic membrane transplantation (AMT). Here, 76 eyes were enrolled in 76 patients with grade 4 AAK. In all eyes, in order to assess preoperatively the efficiency of the limbal epithelial stem cells (LESC), the presence of corneal epithelial cells in confocal microscopy was established. The analyses included: best corrected visual acuity (BCVA), the stage of AAK and the number of corneal quadrants involved in corneal neovascularization (CNV). : Six months after surgery, the mean BCVA was 0.05 and ranged from 0.002 up to 0.1 in both groups. Improvement in BCVA occurred in 94.29% patients when *SK alone* was performed, and in 92.68% when in combination with AMT. There were no statistically significant differences in the effect of therapy depending on the type of surgery, regarding BCVA, stage of AAK and the number of quadrants with CNV. : SK alone is an effective procedure in short outcomes limited to six months for advanced AAK in association with LESC partial efficiency.
PubMed: 38892970
DOI: 10.3390/jcm13113258 -
BMC Ophthalmology Aug 2023Traumatic aniridia occurs when the iris is extruded from the eye and is often accompanied by lens injuries. However, traumatic aniridia due to dislocation of the iris...
BACKGROUND
Traumatic aniridia occurs when the iris is extruded from the eye and is often accompanied by lens injuries. However, traumatic aniridia due to dislocation of the iris into the vitreous cavity without lens damage has never been reported.
CASE PRESENTATION
A 30-year-old man presented with visual loss and pain for 6 h after a thin wire injured his right eyeball. Ophthalmologic examinations manifested a 2 mm full-thickness corneal laceration and total hyphema. An intact clear lens, healthy attached retina, and almost complete iris tissue in the vitreous cavity were found after resolution of hyphema the next day. Further examination revealed that the defect in the zonule below the corneal wound was the path for the iris to enter the vitreous cavity. The patient opted for nonsurgical treatment until pigment granules and opacity were observed in the vitreous cavity after 50 days. Vitrectomy was performed to remove the dislocated iris.
CONCLUSIONS
The presentation of this unique case indicates that the torn iris was displaced to the vitreous cavity with an intact lens and missing local zonula instead of out the corneal laceration after a penetrating injury. The type of injury, mechanism, and force on the spot may contribute to the occurrence of this rare condition. Instead of artificial irises, tinted glasses were more appropriate treatment option for this patient. Peripheral retinal examination was essential in the management of this case. In such cases, the iris in the vitreous cavity should be resected to prevent complications.
Topics: Male; Humans; Adult; Lacerations; Hyphema; Lens, Crystalline; Iris; Corneal Injuries
PubMed: 37605136
DOI: 10.1186/s12886-023-03105-x -
Klinische Monatsblatter Fur... Dec 2023Congenital aniridia is a severe malformation of almost all eye segments. Aniridia-associated keratopathy (AAK) and secondary glaucoma, which occur in more than 50% of...
BACKGROUND
Congenital aniridia is a severe malformation of almost all eye segments. Aniridia-associated keratopathy (AAK) and secondary glaucoma, which occur in more than 50% of affected individuals, are typically progressive and pose a high risk of blindness for patients with congenital aniridia. Our aim was to investigate the effect of glaucoma treatment on AAK in patients of the Homburg Aniridia Center.
METHODS
Our retrospective monocentric study included patients who underwent a comprehensive ophthalmological examination at the Homburg Aniridia Center between June 2003 and January 2022.
RESULTS
There were 556 eyes of 286 subjects (20.1 ± 20.1 years; 45.5% males) included. In 307 (55.2%) eyes of 163 subjects (27.5 ± 16.3 years; 43.1% males), glaucoma was present at the time of examination. The mean intraocular pressure in the glaucoma group was 19.0 mmHg (± 8.0), while in the non-glaucoma group, it was 14.1 mmHg (± 3.6) (p < 0.001). In the glaucoma group, 68 patients used antiglaucomatous topical monotherapy, 51 patients used 2 agents, 41 patients used 3 agents, 7 patients used quadruple therapy, and 140 did not use topical therapy (e.g., after pressure-lowering surgery, pain-free end-stage glaucoma, or incompliance). Patients were classified according to the following stages of AAK: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). The mean stage of AAK was 1.4 (1.2 - 1.5) in the group without eye drops, 1.9 (1.5 - 2.2) in the group with monotherapy, 1.8 (1.5 - 2.1) in the group with 2 drugs, 1.9 (1.5 - 2.2) in the group with 3 drugs, 3.4 (2.3 - 4.6) in the group with 4 drugs, and 3.3 (3.1 - 3.6) after antiglaucomatous surgery. The stage of AAK was significantly positively correlated with the number of pressure-lowering eye drops (p < 0.05) and prior pressure-lowering surgery (p < 0.05). Prostaglandin analogues were not correlated with a higher AAK stage compared to the other drug groups.
CONCLUSIONS
At the Homburg Aniridia Center, patients using topical antiglaucomatous quadruple therapy or who had previously undergone antiglaucomatous surgery had by far the highest AAK stage. The different drug groups had no influence on the AAK stage.
PubMed: 37852284
DOI: 10.1055/a-2194-1580 -
Molecular Systems Biology Jun 2024Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To...
Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combined saturation mutagenesis of the paired domain of PAX6 with a yeast one-hybrid (Y1H) assay in which expression of a PAX6-GAL4 fusion gene drives antibiotic resistance. We quantified binding of more than 2700 single amino-acid variants to two DNA sequence elements. Mutations in DNA-facing residues of the N-terminal subdomain and linker region were most detrimental, as were mutations to prolines and to negatively charged residues. Many variants caused sequence-specific molecular gain-of-function effects, including variants in position 71 that increased binding to the LE9 enhancer but decreased binding to a SELEX-derived binding site. In the absence of antibiotic selection, variants that retained DNA binding slowed yeast growth, likely because such variants perturbed the yeast transcriptome. Benchmarking against known patient variants and applying ACMG/AMP guidelines to variant classification, we obtained supporting-to-moderate evidence that 977 variants are likely pathogenic and 1306 are likely benign. Our analysis shows that most pathogenic mutations in the paired domain of PAX6 can be explained simply by the effects of these mutations on PAX6:DNA association, and establishes Y1H as a generalisable assay for the interpretation of variant effects in transcription factors.
PubMed: 38849565
DOI: 10.1038/s44320-024-00043-8 -
Journal of Community Genetics Feb 2024This qualitative study explored the motivators and barriers for genetic testing for individuals with aniridia. Semi-structured interviews were conducted with 8...
This qualitative study explored the motivators and barriers for genetic testing for individuals with aniridia. Semi-structured interviews were conducted with 8 participants. The main findings highlighted the complex and interrelated factors involved in the decision-making process, including family planning, learning about the specific pathogenic variant of the disease and having access to genetic testing. Benefits and potential risks of genetic testing for aniridia were also discussed. For participants, gaining knowledge about their condition was perceived as a benefit, while administrative issues and concerns around privacy were identified as risks. Increased access to quality information about genetic testing and to the service and associated resources are needed to better support people living with aniridia.
PubMed: 37787878
DOI: 10.1007/s12687-023-00677-5 -
Journal of Clinical Medicine Aug 2023Monoclonal gammopathy (MG) is characterized by monoclonal protein overproduction, potentially leading to the development of hyperviscosity syndrome.
BACKGROUND
Monoclonal gammopathy (MG) is characterized by monoclonal protein overproduction, potentially leading to the development of hyperviscosity syndrome.
OBJECTIVE
To assess retinal circulation using optical coherence tomography angiography (OCTA) parameters in patients with monoclonal gammopathy.
METHODS
OCTA measurements were performed using the Optovue AngioVue system by examining 44 eyes of 27 patients with MG and 62 eyes of 36 control subjects. Superficial and deep retinal capillary vessel density (VD SVP and DVP) in the whole 3 × 3 mm macular and parafoveal area, foveal avascular zone (FAZ) area, and central retinal thickness (CRT) were measured using the AngioAnalytics software. The OCTA parameters were evaluated in both groups using a multivariate regression model, after controlling for the effect of imaging quality (SQ).
RESULTS
There was no significant difference in age between the subjects with monoclonal gammopathy and the controls (63.59 ± 9.33 vs. 58.01 ± 11.46 years; > 0.05). Taking into account the effect of image quality, the VD SVP was significantly lower in the MG group compared to the control group (44.54 ± 3.22% vs. 46.62 ± 2.84%; < 0.05). No significant differences were found between the two groups regarding the other OCTA parameters ( > 0.05).
CONCLUSIONS
A decreased superficial retinal capillary vessel density measured using OCTA in patients with MG suggests a slow blood flow, reduced capillary circulation, and consequent tissue hypoperfusion. An evaluation of retinal circulation using OCTA in cases of monoclonal gammopathy may be a sensitive method for the non-invasive detection and follow-up of early microcirculatory dysfunction caused by increased viscosity.
PubMed: 37629268
DOI: 10.3390/jcm12165227 -
Genes Nov 2023This study investigates the distribution of -associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing gene...
This study investigates the distribution of -associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing gene variants. We contribute novel 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, gene Sanger sequencing, and karyotype analysis. We report novel findings on gene variations, including 67 intragenic 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 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 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.
Topics: Humans; Prevalence; PAX6 Transcription Factor; Aniridia; WAGR Syndrome; Chromosome Deletion
PubMed: 38002984
DOI: 10.3390/genes14112041 -
Current Issues in Molecular Biology Dec 2023This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment...
This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the gene's paired domain is identified. Although this substitution is not in direct contact with DNA, its predicted stabilizing effect on the protein structure challenges the traditional understanding of mutations, suggesting a gain-of-function mechanism. Contrary to classical loss-of-function effects, this gain-of-function hypothesis aligns with research demonstrating PAX6's dosage sensitivity. Gain-of-function mutations, though less common, can lead to diverse phenotypes distinct from aniridia. Our findings emphasize 's multifaceted influence on ocular phenotypes and the importance of genetic variations. We contribute a new perspective on mutations by suggesting a potential gain-of-function mechanism and showcasing the complexities of ocular development. This study sheds light on the intricate interplay of the genetic alterations and regulatory mechanisms underlying complex eye phenotypes. Further research, validation, and collaboration are crucial to unravel the nuanced interactions shaping ocular health and development.
PubMed: 38248310
DOI: 10.3390/cimb46010008 -
Journal of Clinical Medicine Dec 2023To demonstrate the results of ray tracing higher- and lower-order aberrations in pseudophakic eyes with rotationally asymmetrical segment multifocal lenses, total high-...
To demonstrate the results of ray tracing higher- and lower-order aberrations in pseudophakic eyes with rotationally asymmetrical segment multifocal lenses, total high- and low-order aberrations, measured by root mean square value (RMS), refraction, uncorrected distance and uncorrected near visual acuity (UCDVA and UCNVA), and tear break-up time, were measured at scotopic size in 42 eyes of patients implanted with bifocal refractive Mplus15/Mplus30 IOL with +1.5 dpt near addition (42 eyes of patients implanted with Mplus15)/+3.0 dpt near addition (91 eyes of patients implanted with Mplus30), and 107 eyes of control group. No significant differences were noticed between the examined groups concerning UCDVA, UCNVA, and tear break-up time ( < 0.001). Coma and total high-order aberrations were significantly higher for the Mplus30 lens in comparison to the Mplus15 lens and the control group (Coma, Trefoil < 0.001, Secondary Astigmatism = 0.002). The spherical aberrations were significantly higher in the lower-addition lens ( = 0.016) in comparison to the control group and to the higher-addition lens group ( < 0.001). Both intraocular lens models were successful at reaching refractive aim, good distance, and near function with the lower higher-order aberrations for the low-addition lens.
PubMed: 38202246
DOI: 10.3390/jcm13010239