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Rare diseases, or orphan diseases, are those that individually affect a small number of patients, but taken together affect over 300 million people worldwide. They are characterized by their etiological, diagnostic and evolutionary complexity, important morbi-mortality, with high levels of disability that entail and hinder the development of a normal vital subject, not only in those who suffer from them, but also their families; therefore, a comprehensive social health approach is necessary to address this problem.About 80% of rare diseases have a genetic origin, mainly monogenic; thus, genetic testing is mandatory for the confirmation of clinical diagnostics and to ensure correct genetic counseling. Next-generation sequencing (NGS) has enabled a revolution in genetic diseases, specially in rare diseases. However, their complexity makes diagnoses difficult even with the advent of NGS.In this Special Issue, we present several examples of the complexity of genetic diagnosis for most of these diseases and the consequences that genetic testing implies for genetic counseling. There are examples of the genetic heterogeneity of hearing loss, some metabolic and lisosomal disorders, ataxia, Prader–Willi syndrome, and three comprehensive reviews on syndromic retinal dystrophies, the complexity of the molecular diagnosis of neuromuscular disorders, and the value of genetic counseling before and after a genetic test.

Medicine --- retina --- inherited retinal diseases --- syndrome --- Turner syndrome --- mosaicism --- ring chromosomes --- growth hormone deficiency --- pituitary microadenoma --- clinical genetics --- early onset ataxia --- dystonia --- neurodevelopment --- network analysis --- bioinformatics --- ataxia --- phenotype --- child --- NGS --- next generation sequencing --- inborn errors of metabolism --- lysosomal disorders --- neuromuscular disease --- genetic testing --- whole exome sequencing --- Prader–Willi syndrome --- imprinting disorder --- recombinant human growth hormone --- insulin-like growth factor 1 --- HMGLD --- HMGCL --- HMG-CoA lyase deficiency --- inherited metabolic diseases --- familial hearing loss --- multiple diagnoses --- non-syndromic hearing loss --- ACTG1 --- MYH9 --- genetic counselling --- rare diseases --- professional recognition --- hearing loss --- genetic diagnosis --- SLC26A4 --- DFNB4 --- Tuvinians --- Altaians --- Southern Siberia --- Russia --- GSDME --- DFNA5 --- single-exon CNV --- n/a --- Prader-Willi syndrome

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• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Rare diseases, or orphan diseases, are those that individually affect a small number of patients, but taken together affect over 300 million people worldwide. They are characterized by their etiological, diagnostic and evolutionary complexity, important morbi-mortality, with high levels of disability that entail and hinder the development of a normal vital subject, not only in those who suffer from them, but also their families; therefore, a comprehensive social health approach is necessary to address this problem.About 80% of rare diseases have a genetic origin, mainly monogenic; thus, genetic testing is mandatory for the confirmation of clinical diagnostics and to ensure correct genetic counseling. Next-generation sequencing (NGS) has enabled a revolution in genetic diseases, specially in rare diseases. However, their complexity makes diagnoses difficult even with the advent of NGS.In this Special Issue, we present several examples of the complexity of genetic diagnosis for most of these diseases and the consequences that genetic testing implies for genetic counseling. There are examples of the genetic heterogeneity of hearing loss, some metabolic and lisosomal disorders, ataxia, Prader–Willi syndrome, and three comprehensive reviews on syndromic retinal dystrophies, the complexity of the molecular diagnosis of neuromuscular disorders, and the value of genetic counseling before and after a genetic test.

Medicine --- retina --- inherited retinal diseases --- syndrome --- Turner syndrome --- mosaicism --- ring chromosomes --- growth hormone deficiency --- pituitary microadenoma --- clinical genetics --- early onset ataxia --- dystonia --- neurodevelopment --- network analysis --- bioinformatics --- ataxia --- phenotype --- child --- NGS --- next generation sequencing --- inborn errors of metabolism --- lysosomal disorders --- neuromuscular disease --- genetic testing --- whole exome sequencing --- Prader-Willi syndrome --- imprinting disorder --- recombinant human growth hormone --- insulin-like growth factor 1 --- HMGLD --- HMGCL --- HMG-CoA lyase deficiency --- inherited metabolic diseases --- familial hearing loss --- multiple diagnoses --- non-syndromic hearing loss --- ACTG1 --- MYH9 --- genetic counselling --- rare diseases --- professional recognition --- hearing loss --- genetic diagnosis --- SLC26A4 --- DFNB4 --- Tuvinians --- Altaians --- Southern Siberia --- Russia --- GSDME --- DFNA5 --- single-exon CNV --- retina --- inherited retinal diseases --- syndrome --- Turner syndrome --- mosaicism --- ring chromosomes --- growth hormone deficiency --- pituitary microadenoma --- clinical genetics --- early onset ataxia --- dystonia --- neurodevelopment --- network analysis --- bioinformatics --- ataxia --- phenotype --- child --- NGS --- next generation sequencing --- inborn errors of metabolism --- lysosomal disorders --- neuromuscular disease --- genetic testing --- whole exome sequencing --- Prader-Willi syndrome --- imprinting disorder --- recombinant human growth hormone --- insulin-like growth factor 1 --- HMGLD --- HMGCL --- HMG-CoA lyase deficiency --- inherited metabolic diseases --- familial hearing loss --- multiple diagnoses --- non-syndromic hearing loss --- ACTG1 --- MYH9 --- genetic counselling --- rare diseases --- professional recognition --- hearing loss --- genetic diagnosis --- SLC26A4 --- DFNB4 --- Tuvinians --- Altaians --- Southern Siberia --- Russia --- GSDME --- DFNA5 --- single-exon CNV

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Following the implementation of next-generation sequencing technologies (e.g., exome and genome sequencing) in molecular diagnostics, the majority of genetic defects underlying inherited retinal disease (IRD) can readily be identified. In parallel, opportunities to counteract the molecular consequences of these defects are rapidly emerging, providing hope for personalized medicine. ‘Classical’ gene augmentation therapy has been under study for several genetic subtypes of IRD and can be considered a safe and sometimes effective therapeutic strategy. The recent market approval of the first retinal gene augmentation therapy product (LuxturnaTM, for individuals with bi-allelic RPE65 mutations) by the FDA has not only demonstrated the potential of this specific approach, but also opened avenues for the development of other strategies. However, every gene—or even every mutation—may need a tailor-made therapeutic approach, in order to obtain the most efficacious strategy with minimal risks associated. In addition to gene augmentation therapy, other subtypes of molecular therapy are currently being designed and/or implemented, including splice modulation, DNA or RNA editing, optogenetics and pharmacological modulation. In addition, the development of proper delivery vectors has gained strong attention, and should not be overlooked when designing and testing a novel therapeutic approach. In this Special Issue, we aim to describe the current state of the art of molecular therapeutics for IRD, and discuss existing and novel therapeutic strategies, from idea to implementation, and from bench to bedside.

induced pluripotent stem cell (iPSC) --- clustered regularly interspaced short palindromic repeats (CRISPR) --- homology-directed repair (HDR) --- Enhanced S-Cone Syndrome (ESCS) --- NR2E3 --- AAV --- retina --- gene therapy --- dual AAV --- gold nanoparticles --- DNA-wrapped gold nanoparticles --- ARPE-19 cells --- retinal pigment epithelium --- clathrin-coated vesicles --- endosomal trafficking --- retinitis pigmentosa --- autosomal dominant --- G56R --- putative dominant negative effect --- gapmer antisense oligonucleotides --- allele-specific knockdown --- Leber congenital amaurosis and allied retinal ciliopathies --- CEP290 --- Flanders founder c.4723A &gt --- T nonsense mutation --- Cilia elongation --- spontaneous nonsense correction --- AON-mediated exon skipping --- microRNA --- photoreceptors --- rods --- cones --- bipolar cells --- Müller glia --- retinal inherited disorders --- retinal degeneration --- antisense oligonucleotides --- Stargardt disease --- inherited retinal diseases --- splicing modulation --- RNA therapy --- ABCA4 --- iPSC-derived photoreceptor precursor cells --- cyclic GMP --- apoptosis --- necrosis --- drug delivery systems --- translational medicine --- Usher syndrome --- Leber congenital amaurosis --- RPE65 --- nonprofit --- patient registry --- translational --- protein trafficking --- protein folding --- protein degradation --- chaperones --- chaperonins --- heat shock response --- unfolded protein response --- autophagy --- therapy --- IRD --- DNA therapies --- RNA therapies --- compound therapies --- clinical trials --- Retinitis Pigmentosa GTPase Regulator --- adeno-associated viral --- Retinitis Pigmentosa (RP) --- choroideremia --- REP1 --- inherited retinal disease --- treatment --- apical polarity --- crumbs complex --- fetal retina --- PAR complex --- retinal organoids --- retinogenesis --- gene augmentation --- adeno-associated virus (AAV) --- n/a --- Müller glia