The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis

Peter, Virginie G.; Kaminska, Karolina; Santos, Cristina; Quinodoz, Mathieu; Cancellieri, Francesca; Cisarova, Katarina; Gobert, Rosanna Pescini; Rodrigues, Renata; Custódio, Sónia; Paris, Liliana P; Sousa, Ana Berta; Santos, Luisa Coutinho; Rivolta, Carlo

doi:10.1093/pnasnexus/pgad043

Cited by 17 publications

(13 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The next step of this working group will be the genetic analysis of this population. “Hotspots” due to a high rate of consanguinity/homozygosity may allow for an earlier diagnosis, further increasing the difference between municipalities [ 14 , 16 , 23 ]. However, this effect will tend to decrease in the younger population given the migration from the interior to the coast (from rural to urban environments) that occurred in Portugal a few decades ago.…”

Section: Discussionmentioning

confidence: 99%

The socioeconomic epidemiology of inherited retinal diseases in Portugal

Marta,

Marques,

Santos

et al. 2024

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

Background Inherited retinal diseases (IRDs) are a group of rare degenerative disorders of the retina that can lead to blindness from birth to late middle age. Knowing the target population and its resources is essential to better plan support measures. The aim of this study was to evaluate the socioeconomic characteristics of regions in Portugal where IRD patients reside to inform the planning of vision aid and rehabilitation intervention measures. Results This study included 1082 patients from 973 families, aged 3 to 92 years, with a mean age of 44.8 ± 18.1 years. Patients living with an IRD were identified in 190 of the 308 municipalities. According to this study, the estimated IRD prevalence in Portugal was 10.4 per 100,000 inhabitants, and by municipalities, it ranged from 0 to 131.2 per 100,000 inhabitants. Overall, regions with a higher prevalence of IRD have a lower population density (r=-0.371, p < 0.001), a higher illiteracy rate (r = 0.404, p < 0.001) and an overall older population (r = 0.475, p < 0.001). Additionally, there is a lower proportion of doctor per capita (r = 0.350, p < 0.001), higher social security pensions beneficiaries (r = 0.439, p < 0.001), worse water quality for human consumption (r=-0.194, p = 0.008), fewer audiences at the cinema (r=-0.315, p < 0.001) and lower proportion of foreign guests in tourist accommodations (r=-0.287, p < 0.001). Conclusion The number of identified patients with IRD varied between regions. Using data from national statistics (PORDATA), we observed differences in socioeconomic characteristics between regions. Multiple targeted aid strategies can be developed to ensure that all IRD patients are granted full clinical and socioeconomic support.

show abstract

Section: Discussionmentioning

confidence: 99%

The socioeconomic epidemiology of inherited retinal diseases in Portugal

Marta,

Marques,

Santos

et al. 2024

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is estimated that EYS represents one of the most frequently encountered genes in Asian cohorts such as in Korea [15], in an RP cohort in Japan [29], and in a cohort of non-syndromic IRDs in China [17]. It is also remarkable that in a recent Portuguese study EYS represents the most prevalent gene and is considered to be the source of a founder mutation [11]. In the current study, EYS (6.7% of families) is the third most prevalent gene in families, which is uncommon compared to other European studies where it is not often found among the top 5 most prevalent genes.…”

Section: Discussionmentioning

confidence: 99%

Genetics of retinitis pigmentosa and other hereditary retinal disorders in Western Switzerland

Conti,

Vaclavik,

Rivolta

et al. 2023

Ophthalmic Res

View full text Add to dashboard Cite

Introduction: Mutational screening of inherited retinal disorders is prerequisite for gene targeted therapy. Our aim is to report and analyze the proportions of mutations in inherited retinal disease (IRD) causing genes from a single center in Switzerland in order to describe the distribution of IRDs in Western Switzerland. Methods: We conducted a retrospective study of patient records. Criteria for inclusion were residence in Western Switzerland for patients and relatives presenting a clinical diagnosis of IRDs and an established molecular diagnosis managed by the genetics service of the Jules-Gonin Eye Hospital (JGEH) of Lausanne between January 2002 and December 2022. We initially investigated the IRD phenotypes in all patients (full cohort) with a clinical diagnosis, then calculated the distribution of IRD gene mutations in the entire cohort (genetically determined cohort). We analyzed a sub-group that comprised pediatric patients (≤ 18 years of age). In addition, we calculated the distribution of gene mutations within the most represented IRDs. Comprehensive gene screening was performed using a combined approach of different generation of DNA microarray analysis, direct sequencing and Sanger sequencing. Results: The full cohort comprised 899 individuals from 690 families with a clinical diagnosis of IRDs. We identified 400 individuals from 285 families with an elucidated molecular diagnosis (variants in 84 genes) in the genetically determined cohort. The pediatric cohort included 89 individuals from 65 families with an elucidated molecular diagnosis. The molecular diagnosis rate for the genetically determined cohort was 58.2 % (family ratio) and the 5 most frequently implicated genes per family were ABCA4 (11.6 %), USH2A (7.4 %), EYS (6.7 %), PRPH2 (6.3 %) and BEST1 (4.6 %). The pediatric cohort had a family molecular diagnosis rate of 64.4 % and the 5 most common mutated genes per family were RS1 (9.2 %), ABCA4 (7.7 %), CNGB3 (7.7 %), CACNA1F (6.2 %), CEP290 (4.6 %). Conclusions: This study describes the genetic mutation landscape of IRDs in Western Switzerland in order to quantify their disease burden and contribute to a better orientation of the development of future gene targeted therapies.

show abstract

“…Paired-end sequencing on a Novaseq 6000 produced 100-base sequences. Variant filtration and prioritization were performed using an in-house pipeline 33 . Variants in GPATCH11 were identified by selecting rare sequence changes (minor allelic frequency >1%) with highest scores of pathogenicity and consistency with a recessive model of inheritance.…”

Section: Methodsmentioning

confidence: 99%

GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Zanetti,

Fares-Taie,

Amiel

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

G-patch domain-containing proteins have emerged as pivotal regulators of RNA metabolism, and the dysfunction of these proteins has been linked to a large range of phenotypic traits. This study provides compelling evidence that biallelic mutations in GPATCH11 lead to severe early-onset photoreceptor degeneration, neurological issues, and skeletal abnormalities in humans. Analysis of exome datasets from affected individuals of four independent families identified variants in a new gene, GPATCH11. The aim of the study was to determine the genetic source of the patients symptoms and characterize the role of GPATCH11. Using engineered disease variants in mice, we showed abnormal levels of spliceosome components in mutant retinas and substantial splicing deregulation, indicating a role for GPATCH11 in spliceosome homeostasis and splicing activity. Additionally, we identified deregulated gene expression, partly independent of splicing abnormalities, suggesting the involvement of GPATCH11 in transcriptional regulation. The affected genes were found to be related to phototransduction and the transmission of visual messages, protein homeostasis, RNA homeostasis, and cilia metabolism. The presence of GPATCH11 in ciliary basal bodies further suggests a potential role in ciliary functions. Studying GPATCH11 dysfunction elucidates the complex roles of this protein in RNA metabolism, highlighting the significance of GPATCH11 in maintaining proper gene expression and its contributions to various aspects of retinal, neurological, and skeletal function or development. As demonstrated here, studying rare genetic disorders can help to define broader functions beyond the specific disease context, and study provides new insight into the broader roles of GPATCH11.

show abstract

The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis

Cited by 17 publications

References 71 publications

The socioeconomic epidemiology of inherited retinal diseases in Portugal

The socioeconomic epidemiology of inherited retinal diseases in Portugal

Genetics of retinitis pigmentosa and other hereditary retinal disorders in Western Switzerland

GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Contact Info

Product

Resources

About