scholarly journals Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1015 ◽  
Author(s):  
Andrej Zupan ◽  
Ana Fakin ◽  
Saba Battelino ◽  
Martina Jarc-Vidmar ◽  
Marko Hawlina ◽  
...  
Keyword(s):  
Disease Severity ◽  
Nonsense Mutation ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Fundus Autofluorescence ◽  
Usher Syndrome ◽  
Test Methods ◽  
Rapid Screening ◽  
Autofluorescence Imaging ◽  
Phenotype Analysis

Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele.

scholarly journals Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype

2016 ◽  
Vol 8 (2) ◽  
pp. 120-126 ◽  
Author(s):  
Leema Reddy Peddareddygari ◽  
Kinsi Oberoi ◽  
Jaasrini Reddy Vellore ◽  
Raji P. Grewal
Keyword(s):  
Age Of Onset ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Axonal Neuropathy ◽  
Missense Mutations ◽  
Factors Affecting ◽  
Charcot Marie Tooth Disease ◽  
Marked Variability ◽  
Phenotype Analysis ◽  
Family Gene

Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions.

scholarly journals Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis

2021 ◽  
Author(s):  
David R Blair ◽  
Thomas J Hoffmann ◽  
Joseph T Shieh
Keyword(s):  
Disease Severity ◽  
Quantitative Traits ◽  
Phenotypic Variability ◽  
Small Sample ◽  
Mendelian Disease ◽  
Contributing Factors ◽  
Full Spectrum ◽  
Association Analyses ◽  
Mendelian Diseases ◽  
Phenotype Analysis

Clinical heterogeneity is common in Mendelian disease, but small sample sizes make it difficult to identify specific contributing factors. However, if a rare disease represents the severely affected extreme of a spectrum of phenotypic variation, then modifier effects may be apparent within a larger subset of the population. Analyses that take advantage of this full spectrum could have substantially increased power. To test this, we developed cryptic phenotype analysis (CPA), a model-based approach that uses symptom data to infer latent quantitative traits that capture disease-related phenotypic variability. By applying this approach to 50 Mendelian diseases in two large cohorts of patients, we found that these quantitative traits reliably captured disease severity. We then conducted genome-wide association analyses for five of the inferred cryptic phenotypes, uncovering common variation that was predictive of Mendelian disease-related diagnoses and outcomes. Overall, this study highlights the utility of computationally derived phenotypes and biobank-scale cohorts for investigating the complex genetic architecture of Mendelian diseases.

scholarly journals Modeling of atrophy size trajectories: variable transformation, prediction and age-of-onset estimation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Charlotte Behning ◽  
Monika Fleckenstein ◽  
Maximilian Pfau ◽  
Christine Adrion ◽  
Lukas Goerdt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Age Of Onset ◽  
Fundus Autofluorescence ◽  
Model Fitting ◽  
Information Criterion ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Autofluorescence Imaging ◽  
Statistical Regression ◽  
Age Related

Abstract Background To model the progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD) by building a suitable statistical regression model for GA size measurements obtained from fundus autofluorescence imaging. Methods Based on theoretical considerations, we develop a linear mixed-effects model for GA size progression that incorporates covariable-dependent enlargement rates as well as correlations between longitudinally collected GA size measurements. To capture nonlinear progression in a flexible way, we systematically assess Box-Cox transformations with different transformation parameters λ. Model evaluation is performed on data collected for two longitudinal, prospective multi-center cohort studies on GA size progression. Results A transformation parameter of λ=0.45 yielded the best model fit regarding the Akaike information criterion (AIC). When hypertension and hypercholesterolemia were included as risk factors in the model, they showed an association with progression of GA size. The mean estimated age-of-onset in this model was 67.21±6.49 years. Conclusions We provide a comprehensive framework for modeling the course of uni- or bilateral GA size progression in longitudinal observational studies. Specifically, the model allows for age-of-onset estimation, identification of risk factors and prediction of future GA size. A square-root transformation of atrophy size is recommended before model fitting.

scholarly journals Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

2018 ◽  
Vol 19 (8) ◽  
pp. 2196 ◽  
Author(s):  
Marco Nassisi ◽  
Saddek Mohand-Saïd ◽  
Claire-Marie Dhaenens ◽  
Fiona Boyard ◽  
Vanessa Démontant ◽  
...  
Keyword(s):  
Near Infrared ◽  
Age Of Onset ◽  
Fundus Autofluorescence ◽  
Mutation Spectrum ◽  
Fundus Photography ◽  
Heterozygous Mutation ◽  
Autofluorescence Imaging ◽  
Stargardt Disease ◽  
Full Field ◽  
Uncertain Significance

Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.

scholarly journals Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

2021 ◽  
Vol 22 (5) ◽  
pp. 2374
Author(s):  
Laura Kuehlewein ◽  
Ditta Zobor ◽  
Katarina Stingl ◽  
Melanie Kempf ◽  
Fadi Nasser ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Genetic Testing ◽  
Retinitis Pigmentosa ◽  
Fundus Autofluorescence ◽  
Retinal Disease ◽  
New Drugs ◽  
Autofluorescence Imaging ◽  
Full Field ◽  
Tertiary Referral Center ◽  
The Right

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

scholarly journals Fundus autofluorescence and optical coherence tomography in relation to visual function in Usher syndrome type 1 and 2

2012 ◽  
Vol 75 ◽  
pp. 60-70 ◽  
Author(s):  
Ana Fakin ◽  
Martina Jarc-Vidmar ◽  
Damjan Glavač ◽  
Crystel Bonnet ◽  
Christine Petit ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Visual Function ◽  
Fundus Autofluorescence ◽  
Usher Syndrome ◽  
Syndrome Type ◽  
Optical Coherence ◽  
Usher Syndrome Type

scholarly journals Structural evaluation in inherited retinal diseases

2021 ◽  
pp. bjophthalmol-2021-319228
Author(s):  
Malena Daich Varela ◽  
Burak Esener ◽  
Shaima A Hashem ◽  
Thales Antonio Cabral de Guimaraes ◽  
Michalis Georgiou ◽  
...  
Keyword(s):  
Adaptive Optics ◽  
Fundus Autofluorescence ◽  
Standard Of Care ◽  
Laser Speckle ◽  
Fundus Photography ◽  
Laser Speckle Flowgraphy ◽  
Retinal Diseases ◽  
Autofluorescence Imaging ◽  
Structural Evaluation ◽  
Fundus Imaging

Ophthalmic genetics is a field that has been rapidly evolving over the last decade, mainly due to the flourishing of translational medicine for inherited retinal diseases (IRD). In this review, we will address the different methods by which retinal structure can be objectively and accurately assessed in IRD. We review standard-of-care imaging for these patients: colour fundus photography, fundus autofluorescence imaging and optical coherence tomography (OCT), as well as higher-resolution and/or newer technologies including OCT angiography, adaptive optics imaging, fundus imaging using a range of wavelengths, magnetic resonance imaging, laser speckle flowgraphy and retinal oximetry, illustrating their utility using paradigm genotypes with on-going therapeutic efforts/trials.

scholarly journals Fundus autofluorescence imaging of macular star

2009 ◽  
Vol 87 (6) ◽  
pp. 690-691 ◽  
Author(s):  
Ali Ayata ◽  
Melih Ünal ◽  
Dilaver Erşanlı ◽  
Sinan Tatlıpınar
Keyword(s):  
Fundus Autofluorescence ◽  
Autofluorescence Imaging ◽  
Macular Star

scholarly journals Camptocormia in patients with multiple system atrophy at different disease durations: frequency and related factors

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ling Yu Zhang ◽  
Bei Cao ◽  
Qian-Qian Wei ◽  
Ru Wei Ou ◽  
Bi Zhao ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Disease Severity ◽  
Disease Duration ◽  
Rating Scale ◽  
Cox Regression ◽  
Age Of Onset ◽  
Older Age ◽  
Related Factors ◽  
Cox Regression Analysis ◽  
The Impact

Abstract Background Camptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated. Methods A total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3–5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used. Results In the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3–5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3–5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463). Conclusion The frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease.

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