A genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.

Background: Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.

Methods: Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization.

Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene.

Background: Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) in certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. EYS is one of the largest genes (~ 2 Mb) expressed in the retina, in which structural variants (SVs) represent a common cause of disease. However, their identification using short-read sequencing (SRS) is not always feasible.

Establishment and Comprehensive Characterization of a Novel Preclinical Platform of Metastatic Retinoblastoma for Therapeutic Developments.

Purpose: Although there have been improvements in the management of metastatic retinoblastoma, most patients do not survive, and all patients suffer from multiple short- and long-term treatment toxicities. Reliable and informative models to assist clinicians are needed. Thus we developed and comprehensively characterized a novel preclinical platform of primary cell cultures and xenograft models of metastatic retinoblastoma to provide insights into the molecular biology underlying metastases and to perform drug screening for the identification of hit candidates with the highest potential for clinical translation.

Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients.

Purpose: To describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients.

Methods: This retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of and other phenocopying genes (, , and ) was performed in 97 STGD patients.

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt.

Clinical, Genomic, and Pharmacological Study of -Amplified Wild-Type Metastatic Retinoblastoma.

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in gene with high-level amplification of (ampl+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of ampl+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common high amplification and chromosome 16q and 17p loss.

Genomic and Transcriptomic Tumor Heterogeneity in Bilateral Retinoblastoma.

Importance: Comprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics.

Objective: To compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma.

Design, Setting, And Participants: In this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation.

Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel.

EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.

Using a positional cloning approach supported by comparative genomics, we have identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa. Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents, but is well conserved from Drosophila to man and is likely to have a role in the modeling of retinal architecture.

Melatonin prevents hydrogen peroxide-induced Bax expression in cultured rat astrocytes.

During oxidative stress, cell apoptosis is promoted through the mitochondrial death pathway. Increased reactive oxygen species (ROS) are linked to excess cell loss and mediate the induction of apoptosis in various cell types. However, the role of ROS in the apoptotic pathway has not been clearly established.