Publications by authors named "Marta Del Pozo Valero"

, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype-phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families.

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Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%).

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Background: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs).

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Inherited retinal dystrophies (IRDs) can be caused by variants in more than 280 genes. The ATP-binding cassette transporter type A4 () gene is one of these genes and has been linked to Stargardt disease type 1 (STGD1), fundus flavimaculatus, cone-rod dystrophy (CRD), and pan-retinal CRD. Approximately 25% of the reported variants affect RNA splicing.

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Purpose: To describe the genetic and clinical spectrum of GUCY2D-associated retinopathies and to accurately establish their prevalence in a large cohort of patients.

Design: Retrospective case series.

Methods: Institutional study of 47 patients from 27 unrelated families with retinal dystrophies carrying disease-causing GUCY2D variants from the Fundación Jiménez Díaz hospital dataset of 8000 patients.

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Screening for pathogenic variants in the diagnosis of rare genetic diseases can now be performed on all genes thanks to the application of whole exome and genome sequencing (WES, WGS). Yet the repertoire of gene-disease associations is not complete. Several computer-based algorithms and databases integrate distinct gene-gene functional networks to accelerate the discovery of gene-disease associations.

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Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality.

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The introduction of NGS in genetic diagnosis has increased the repertoire of variants and genes involved and the amount of genomic information produced. We built an allelic-frequency (AF) database for a heterogeneous cohort of genetic diseases to explore the aggregated genomic information and boost diagnosis in inherited retinal dystrophies (IRD). We retrospectively selected 5683 index-cases with clinical exome sequencing tests available, 1766 with IRD and the rest with diverse genetic diseases.

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Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied.

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Purpose: To assess the potential of next-generation sequencing (NGS) technologies to characterize cases diagnosed with autosomal recessive (ar) or sporadic (s) macular dystrophies (ar/sMD) and describe their mutational spectrum.

Methods: A cohort of 1036 families was classified according to their suspected clinical diagnosis-Stargardt disease (STGD), cone and cone-rod dystrophy (CCRD) or other maculopathies (otherMD). Molecular studies included genotyping microarrays, Sanger sequencing, NGS, and sequencing of intronic regions of the ABCA4 gene.

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Clinical exome (CE) sequencing has become a first-tier diagnostic test for hereditary diseases; however, its diagnostic rate is around 30-50%. In this study, we aimed to increase the diagnostic yield of CE using a custom reanalysis algorithm. Sequencing data were available for three cohorts using two commercial protocols applied as part of the diagnostic process.

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Introduction: Biallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals progress to severe disease, with 50% of patients becoming legally blind by 20 years of age. Deeper knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed.

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Mutations in Retinitis pigmentosa GTPase regulator gene (RPGR) are the most common cause of X-linked retinitis pigmentosa (RP). Almost 60% of disease-causing RPGR mutations are located in ORF-15 region which cannot be detected by Next Generation Sequencing (NGS) due to the existence of highly repetitive regions. An Iranian family with a priori diagnosis of autosomal dominant RP was studied by Sanger sequencing of ORF15 of RPGR gene after an inconclusive NGS result.

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Background: Bardet-Biedl syndrome is an autosomal recessive disease characterized by rod-cone dystrophy, postaxial polydactyly, kidney defects, obesity, mental retardation and hypogonadism. Here, we report different genotypes in two Bardet-Biedl syndrome affected sisters with a different clinical phenotype regarding severity.

Materials And Methods: The proband of the family was examined by Next Generation Sequencing (NGS) using clinical exome and filtering by syndromic and non-syndromic genes associated with retinal dystrophies.

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Inherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests.

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Article Synopsis
  • Inherited retinal diseases (IRDs) involve the dysfunction or loss of photoreceptors and show significant clinical and genetic variability; this study aimed to detail the genetic landscape of IRDs in a large cohort of Spanish patients.
  • Over 6,000 individuals from 4,403 families were analyzed, with 53.2% of families genetically characterized, revealing 1,549 likely pathogenic variants across 142 genes, with retinitis pigmentosa being the most common phenotype (55.6% of families).
  • The study identified key genes linked to various IRD forms and highlighted frequent variants, providing valuable insights for genetic diagnosis, counseling, and potential therapies for the Spanish population and related groups.
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Importance: The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management.

Objective: To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1.

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Purpose: To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD).

Design: Cohort study.

Methods: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies.

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Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.

Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method.

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Pathogenic variants in the ATP-binding cassette transporter A4 (ABCA4) gene cause a continuum of retinal disease phenotypes, including Stargardt disease. Noncanonical splice site (NCSS) and deep-intronic variants constitute a large fraction of disease-causing alleles, defining the functional consequences of which remains a challenge. We aimed to determine the effect on splicing of nine previously reported or unpublished NCSS variants, one near exon splice variant and nine deep-intronic variants in ABCA4, using in vitro splice assays in human embryonic kidney 293T cells.

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Purpose: To describe the genetic and phenotypic characteristics of a cohort of patients with PROM1 variants.

Design: Case-case study.

Methods: We screened a cohort of 2216 families with inherited retinal dystrophies using classical molecular techniques and next-generation sequencing approaches.

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Article Synopsis
  • The study investigated the genetic origins of sporadic retinitis pigmentosa (sRP) in a large group of 877 unrelated Spanish patients with no family history of the disease.
  • Using advanced genetic techniques, they identified causative genetic variants in about 38% of the patients, with a significant number being de novo mutations.
  • The findings underscore the importance of next-generation sequencing (NGS) for diagnosing sRP and highlight the need for thorough gene screening to improve family counseling and potential gene therapy options.
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