Genes

Research

11 pages, 503 KiB

Open AccessArticle

Searching for Effective Methods of Diagnosing Nervous System Lesions in Patients with Alström and Bardet–Biedl Syndromes

by Arleta Waszczykowska, Krzysztof Jeziorny, Dobromiła Barańska, Katarzyna Matera, Aleksandra Pyziak-Skupien, Michał Ciborowski and Agnieszka Zmysłowska

Genes 2023, 14(9), 1784; https://doi.org/10.3390/genes14091784 - 10 Sep 2023

Viewed by 1180

Abstract

Bardet–Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators [...] Read more.

Bardet–Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group (p = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% (p = 0.0004), 35% (p = 0.0008), and 28% (p = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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12 pages, 922 KiB

Open AccessArticle

Polygenic Risk Score and Rare Variant Burden Identified by Targeted Sequencing in a Group of Patients with Pigment Epithelial Detachment in Age-Related Macular Degeneration

by Anna Wąsowska, Adam Sendecki, Anna Boguszewska-Chachulska and Sławomir Teper

Genes 2023, 14(9), 1707; https://doi.org/10.3390/genes14091707 - 27 Aug 2023

Cited by 3 | Viewed by 2044

Abstract

A subset of ophthalmic imaging examination results from 334 patients were subjected to reanalysis to identify a specific group of patients with pigment epithelial detachment (PED) in at least one eye. Overall, we found a subgroup of 47 patients manifesting PED and studied [...] Read more.

A subset of ophthalmic imaging examination results from 334 patients were subjected to reanalysis to identify a specific group of patients with pigment epithelial detachment (PED) in at least one eye. Overall, we found a subgroup of 47 patients manifesting PED and studied their genotypes in comparison to those of patients with age-related macular degeneration without PED and healthy controls. We established a polygenic risk score that allowed the explanation of 16.3% of the variation within the disease. The highest predictive value was achieved for a model consisting of six non-coding variants: rs760306 (BEST1), rs148662546 (BEST1), rs11569560 (C3), rs74600252 (GUCA1B), rs2240688 (PROM1), and rs185507582 (TCF4). The risk of PED occurrence was found to be the highest in the first tercile, showing a 7.89-fold higher risk compared to the third tercile for AMD without PED (95% CI: 2.87; 21.71, p < 0.001) and a 7.22-fold higher risk compared to the healthy controls (95% CI: 2.60; 20.06, p < 0.001). In addition, we focused on rare variants in targeted genes. The rare variants’ burden was compared among the groups, but no statistical significance was observed in the number of rare variants, predicted functional effects, or pathogenicity classification. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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15 pages, 8977 KiB

Open AccessArticle

Progressive Cone-Rod Dystrophy and RPE Dysfunction in Mitf^mi/+ Mice

by Andrea García-Llorca, Knútur Haukstein Ólafsson, Arnór Thorri Sigurdsson and Thor Eysteinsson

Genes 2023, 14(7), 1458; https://doi.org/10.3390/genes14071458 - 17 Jul 2023

Cited by 3 | Viewed by 1792

Abstract

Mutations in the mouse microphthalmia-associated transcription factor (Mitf) gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse Mitf gene [...] Read more.

Mutations in the mouse microphthalmia-associated transcription factor (Mitf) gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse Mitf gene and a variety of human retinal diseases, including Waardenburg type 2 and Tietz syndromes. Although there is evidence showing that mice with the homozygous Mitf^mi mutation manifest microphthalmia and osteopetrosis, there are limited or no data on the effects of the heterozygous condition in the eye. Mitf mice can therefore be regarded as an important model system for the study of human disease. Thus, we characterized Mitf^mi/+ mice at 1, 3, 12, and 18 months old in comparison with age-matched wild-type mice. The light- and dark-adapted electroretinogram (ERG) recordings showed progressive cone-rod dystrophy in Mitf^mi/+ mice. The RPE response was reduced in the mutant in all age groups studied. Progressive loss of pigmentation was found in Mitf^mi/+ mice. Histological retinal sections revealed evidence of retinal degeneration in Mitf^mi/+ mice at older ages. For the first time, we report a mouse model of progressive cone-rod dystrophy and RPE dysfunction with a mutation in the Mitf gene. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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23 pages, 744 KiB

Open AccessArticle

A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing

by Maria Areblom, Sten Kjellström, Sten Andréasson, Anders Öhberg, Lotta Gränse and Ulrika Kjellström

Genes 2023, 14(7), 1413; https://doi.org/10.3390/genes14071413 - 8 Jul 2023

Viewed by 1776

Abstract

In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved [...] Read more.

In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were ABCA4 (16.5%), RPGR (6%), CEP290 (6%), and RS1 (5.5%). Other prevalent genes were CACNA1F (3%), PROM1 (3%), CHM (3%), and NYX (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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13 pages, 2723 KiB

Open AccessArticle

Genetic and Clinical Characterization of Danish Achromatopsia Patients

by Mette Kjøbæk Gundestrup Andersen, Mette Bertelsen, Karen Grønskov, Susanne Kohl and Line Kessel

Genes 2023, 14(3), 690; https://doi.org/10.3390/genes14030690 - 10 Mar 2023

Cited by 6 | Viewed by 2357

Abstract

Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This [...] Read more.

Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945–2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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Review

Jump to: Research, Other

20 pages, 2274 KiB

Open AccessReview

Molecular Mechanisms Governing Sight Loss in Inherited Cone Disorders

by Chloe Brotherton and Roly Megaw

Genes 2024, 15(6), 727; https://doi.org/10.3390/genes15060727 - 1 Jun 2024

Viewed by 1775

Abstract

Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour [...] Read more.

Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone–rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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17 pages, 1228 KiB

Open AccessReview

Inherited Retinal Diseases and Retinal Organoids as Preclinical Cell Models for Inherited Retinal Disease Research

by Kristen E. Ashworth, Jessica Weisbrod and Brian G. Ballios

Genes 2024, 15(6), 705; https://doi.org/10.3390/genes15060705 - 28 May 2024

Viewed by 2373

Abstract

Inherited retinal diseases (IRDs) are a large group of genetically and clinically diverse blinding eye conditions that result in progressive and irreversible photoreceptor degeneration and vision loss. To date, no cures have been found, although strides toward treatments for specific IRDs have been [...] Read more.

Inherited retinal diseases (IRDs) are a large group of genetically and clinically diverse blinding eye conditions that result in progressive and irreversible photoreceptor degeneration and vision loss. To date, no cures have been found, although strides toward treatments for specific IRDs have been made in recent years. To accelerate treatment discovery, retinal organoids provide an ideal human IRD model. This review aims to give background on the development and importance of retinal organoids for the human-based in vitro study of the retina and human retinogenesis and retinal pathologies. From there, we explore retinal pathologies in the context of IRDs and the current landscape of IRD treatment discovery. We discuss the usefulness of retinal organoids in this context (as a patient-derived cell model for IRDs) to precisely understand the pathogenesis and potential mechanisms behind a specific IRD-causing variant of interest. Finally, we discuss the importance and promise of retinal organoids in treatment discovery for IRDs, now and in the future. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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Other

Jump to: Research, Review

9 pages, 2227 KiB

Open AccessBrief Report

Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia

by Rebeca A. S. Amaral, Fabiana L. Motta, Olivia A. Zin, Mariana M. da Palma, Gabriela D. Rodrigues and Juliana M. F. Sallum

Genes 2023, 14(6), 1296; https://doi.org/10.3390/genes14061296 - 20 Jun 2023

Viewed by 1698

Abstract

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes encoding proteins composing the cone phototransduction cascade (CNGA3, CNGB3, PDE6C, PDE6H, [...] Read more.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes encoding proteins composing the cone phototransduction cascade (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2) and of the unfolded protein response (ATF6) have been related to ACHM cases, while CNGA3 and CNGB3 alone are responsible for most cases. Herein, we provide a clinical and molecular overview of 42 Brazilian patients from 38 families affected with ACHM related to biallelic pathogenic variants in the CNGA3 and CNGB3 genes. Patients’ genotype and phenotype were retrospectively evaluated. The majority of CNGA3 variants were missense, and the most prevalent CNGB3 variant was c.1148delC (p.Thr383Ilefs*13), resulting in a frameshift and premature stop codon, which is compatible with previous publications in the literature. A novel variant c.1893T>A (p.Tyr631*) in the CNGB3 gene is reported for the first time in this study. A great variability in morphologic findings was observed in our patients, although no consistent correlation with age and disease stage in OCT foveal morphology was found. The better understanding of the genetic variants landscape in the Brazilian population will help in the diagnosis of this disease. Full article

(This article belongs to the Special Issue Genetics in Retinal Diseases)

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