PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is a common, age-related cause of visual impairment. This systematic review synthesizes evidence from the literature on artificial intelligence (AI) models developed for the diagnosis and management of FECD. METHODS: We conducted a systematic literature search in MEDLINE, PubMed, Web of Science, and Scopus from January 1, 2000, to June 31, 2024. Full-text studies utilizing AI for various clinical contexts of FECD management were included. Data extraction covered model development, predicted outcomes, validation, and model performance metrics. We graded the included studies using the Quality Assessment of Diagnostic Accuracies Studies 2 tool. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. RESULTS: Nineteen studies were analyzed. Primary AI algorithms applied in FECD diagnosis and management included neural network architectures specialized for computer vision, utilized on confocal or specular microscopy images, or anterior segment optical coherence tomography images. AI was employed in diverse clinical contexts, such as assessing corneal endothelium and edema and predicting post-corneal transplantation graft detachment and survival. Despite many studies reporting promising model performance, a notable limitation was that only three studies performed external validation. Bias introduced by patient selection processes and experimental designs was evident in the included studies. CONCLUSIONS: Despite the potential of AI algorithms to enhance FECD diagnosis and prognostication, further work is required to evaluate their real-world applicability and clinical utility. TRANSLATIONAL RELEVANCE: This review offers critical insights for researchers, clinicians, and policymakers, aiding their understanding of existing AI research in FECD management and guiding future health service strategies.

• MeSH
• Fuchsova endoteliální dystrofie * diagnóza   terapie   MeSH
• lidé MeSH
• optická koherentní tomografie metody   MeSH
• umělá inteligence * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH

IMPORTANCE: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies. OBJECTIVE: To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study recruited 894 individuals with FECD at Moorfields Eye Hospital (London) and General University Hospital (Prague) from September 2009 to July 2023. Ancestry was inferred from genome-wide single nucleotide polymorphism array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed polymerase chain reaction. One or more expanded alleles (≥50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced. MAIN OUTCOMES AND MEASURES: Association between variants in FECD-associated genes, demographic data, and age at first keratoplasty. RESULTS: Within the total cohort (n = 894), 77.3% of patients were Exp+. Most European (668 of 829 [80.6%]) and South Asian (14 of 22 [63.6%]) patients were Exp+. The percentage of female patients was higher (151 [74.4%]) in the Exp- cohort compared to the Exp+ cohort (395 [57.2%]; difference, 17.2%; 95% CI, 10.1%-24.3%; P < .001). The median (IQR) age at first keratoplasty of the Exp + patients (68.2 years [63.2-73.6]) was older than the Exp- patients (61.3 years [52.6-70.4]; difference, 6.5 years; 95% CI, 3.4-9.7; P < .001). The CTG18.1 repeat length of the largest expanded allele within the Exp+ group was inversely correlated with the age at first keratoplasty (β, -0.087; 95% CI, -0.162 to -0.012; P = .02). The ratio of biallelic to monoallelic expanded alleles was higher in the FECD cohort (1:14) compared to an unaffected control group (1:94; P < .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, <0.01; combined annotation dependent depletion, >15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%). CONCLUSIONS AND RELEVANCE: In this multicenter cohort study among individuals with FECD, CTG18.1 expansions were present in most European and South Asian patients, while CTG18.1 repeat length and zygosity status were associated with modifications in disease severity and penetrance. Known disease-associated genes accounted for only a minority of Exp- cases, with unknown risk factors associated with disease in the rest of this subgroup. These data may have implications for future FECD gene-targeted therapy development.

• MeSH
• celogenomová asociační studie MeSH
• dospělí MeSH
• Fuchsova endoteliální dystrofie * genetika   chirurgie   epidemiologie   diagnóza   MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

The Roma people have a complex demographic history shaped by their recent dispersal from a South Asian origin into Europe, accompanied by continuous population bottlenecks and gene flow. After settling in the Balkans around 1,000 years ago, the Roma gradually dispersed across Europe, and approximately 500 years ago, they established in the Iberian Peninsula what is now one of the largest Roma populations in Western Europe. Focusing specifically on the Iberian Roma, we conducted the most comprehensive genome-wide analysis of European Roma populations to date. Using allele frequency and haplotype-based methods, we analysed 181 individuals to investigate their genetic diversity, social dynamics, and migration histories at both continental and local scales. Our findings demonstrate significant gene flow from populations encountered during the Roma's dispersal and confirm their South Asian origins. We show that, between the 14th and 19th centuries, the Roma spread westward from the Balkans in various waves, with multiple admixture events. Furthermore, our findings refute previous hypotheses of a North African dispersal route into Iberia and genetic connections to Jewish populations. The Iberian Roma exhibit ten times greater genetic differentiation compared to non-Roma Iberians, indicating significant regional substructure. Additionally, we provide the first genetic evidence of assortative mating within Roma groups, highlighting distinct mating patterns and suggesting a gradual shift towards increased integration with non-Roma individuals. This study significantly enhances our understanding of how demographic history and complex genetic structure have shaped the genetic diversity of Roma populations, while also highlighting the influence of their evolving social dynamics.

• MeSH
• frekvence genu MeSH
• genetická variace MeSH
• haplotypy MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• migrace lidstva MeSH
• populační genetika * MeSH
• Romové * genetika   MeSH
• tok genů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Španělsko MeSH

Corneal dystrophies are a group of predominantly rare inherited disorders. They are by definition bilateral, relatively symmetrical, and without systemic involvement, affecting corneal transparency and/or refraction. Traditional classification of corneal dystrophies is based on slit-lamp appearance, affected corneal layer and histological features. Molecular genetics has provided ultimate proof for the existence of distinct corneal dystrophies and discarded duplicates in their terminology. Currently, there are at least 16 genes with identified pathogenic variants implicated in corneal dystrophies. Herein, we summarise contemporary knowledge on genotype-phenotype correlations of corneal dystrophies, including a critical review of some reported variants, along with the understanding of the underlying pathogenic dystrophic process; essential knowledge for the development of targeted therapies.

• MeSH
• dědičné dystrofie rohovky * genetika   terapie   MeSH
• fenotyp MeSH
• genetické asociační studie * MeSH
• genotyp MeSH
• lidé MeSH
• molekulární biologie MeSH
• mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Klíčová slova
• sklerokornea,
• MeSH
• abnormality očí * diagnostické zobrazování   genetika   patologie   MeSH
• dědičné nemoci očí * diagnostické zobrazování   genetika   patologie   MeSH
• dospělí MeSH
• lidé MeSH
• mutace MeSH
• optická koherentní tomografie MeSH
• přední segment oční abnormality   MeSH
• předškolní dítě MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

• MeSH
• aniridie * diagnostické zobrazování   genetika   patologie   MeSH
• dítě MeSH
• lidé MeSH
• optická koherentní tomografie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

BACKGROUND: The oculo-facio-cardio-dental syndrome (OFCD) is an ultra-rare multiple congenital anomaly. This report describes clinical findings emphasising dental phenotype in five, molecularly confirmed, female cases from two Czech families. CASE PRESENTATION: Dental examinations were carried out. An orthopantomogram was taken in three patients, and all patients' intraoral cavities and teeth were photographed. Exome sequencing was performed in both probands. Results were validated by Sanger DNA sequencing which was also used to follow segregation of the variants in first-degree relatives. Dental abnormalities and congenital cataracts were present in all five cases, whilst other signs were variable and included facial dysmorphism, microphthalmia, and cardiac and skeletal abnormalities. Two individuals had cleft lip and/or cleft palate. Radiculomegaly occurred in three patients with permanent teeth and was diagnosed on orthopantomograms. Two patients had agenesis of permanent teeth. Malocclusion was also present in two patients due to crowding and a Class III malocclusion and mandibular overjet. De novo novel pathogenic variants in the BCOR gene were identified; c.2382del p.(Lys795Argfs*12) and c.3914dup p.(Gln1306Alafs*20) and co-segregated with the disease in each family. CONCLUSIONS: The OFCD syndrome has a unique dental phenotype and dentists should be aware of signs of this ultra-rare genetic disorder. All patients with congenital cataracts and dental abnormalities, including those without a family history, should be referred for genetic testing and indicated to specialised dental care.

• MeSH
• abnormality očí genetika   MeSH
• abnormality zubů * genetika   MeSH
• defekty srdečního septa MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• genetické nemoci vázané na chromozom X MeSH
• katarakta genetika   vrozené   MeSH
• lidé MeSH
• mikroftalmie * genetika   MeSH
• mladiství MeSH
• mnohočetné abnormality genetika   MeSH
• protoonkogenní proteiny * genetika   MeSH
• rentgendiagnostika panoramatická MeSH
• represorové proteiny * genetika   MeSH
• rodokmen MeSH
• vrozené srdeční vady genetika   komplikace   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH

Dědičná onemocnění sítnice (inherited retinal disease, IRD) představují v rozvinutých zemích druhou nejčastější příčinu slepoty u dětí. Nedávné schválení genové terapie pro pacienty s mutacemi v genu RPE65 představuje milník v terapii těchto doposud neléčitelných onemocnění. V České republice není spektrum fenotypů a mutací způsobujících IRD u dětí známo, neexistují žádné registry. Cílem projektu je identifikovat dětské pacienty s IRD a vytvořit pro ně program multidisciplinární péče, v jehož rámci bude provedena detailní charakterizace klinických nálezů a symptomatická péče. U případů, kde rutinní vyšetření v diagnostické laboratoři nepovede k odhalení patogenních mutací, provedeme celogenomové sekvenování a funkční studie k posouzení dopadu odhalených variant. Očekáváme, že se nám podaří významně přispět ke znalostem o IRD s manifestací v dětském věku. Projekt bude mít přímý přínos pacienty a jejich rodiny spočívající ve zlepšení genetického poradenství, včasnou léčbu extraokulárních projevů a zvýšení možnosti k přístupu k cíleným terapiím, které jsou v současné době vyvíjeny.; Inherited retinal disease (IRD) represents in developed countries the second most common cause of legal blindness in children. The recent approval of gene therapy for RPE65-associated IRD paves the way to the treatment. IRD exhibit a vast clinical and genetic heterogeneity and can be either isolated conditions or a sign of a multiorgan disease. In the Czech Republic the spectrum of phenotypes and disease-causing mutations in children with IRD is unknown. The aim of the project is to identify Czech children with IRD and to establish a multidisciplinary care centre for them. This will include deep phenotyping and symptomatic management. In cases unsolved after diagnostic testing genome sequencing and functional studies will be performed to assess the effect of identified variants. We expect to significantly aid to the knowledge on childhood-onset IRD. Our project will directly impact patients and their families via improved counseling, timely management of extraocular disease and most importantly access to targeted therapies when available, which is the ultimate goal of the project.

• Klíčová slova
• novel therapies, genomové sekvenování, genome sequencing, genetické testování, Genetic Testing, retinopatie dětského věku, primární ciliopatie, syndromová onemocnění, funkční studie, mechanismus onemocňení, Childhood-onset inherited retinal disease, primary ciliopathy, syndromic disease, functional studies, disease mechanisms, nové terapeutické přístupy,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Fuchs endothelial corneal dystrophy (FECD) is the most common repeat-mediated disease in humans. It exclusively affects corneal endothelial cells (CECs), with ≤81% of cases associated with an intronic TCF4 triplet repeat (CTG18.1). Here, we utilise optical genome mapping (OGM) to investigate CTG18.1 tissue-specific instability to gain mechanistic insights. METHODS: We applied OGM to a diverse range of genomic DNAs (gDNAs) from patients with FECD and controls (n = 43); CECs, leukocytes and fibroblasts. A bioinformatics pipeline was developed to robustly interrogate CTG18.1-spanning DNA molecules. All results were compared with conventional polymerase chain reaction-based fragment analysis. FINDINGS: Analysis of bio-samples revealed that expanded CTG18.1 alleles behave dynamically, regardless of cell-type origin. However, clusters of CTG18.1 molecules, encompassing ∼1800-11,900 repeats, were exclusively detected in diseased CECs from expansion-positive cases. Additionally, both progenitor allele size and age were found to influence the level of leukocyte-specific CTG18.1 instability. INTERPRETATION: OGM is a powerful tool for analysing somatic instability of repeat loci and reveals here the extreme levels of CTG18.1 instability occurring within diseased CECs underpinning FECD pathophysiology, opening up new therapeutic avenues for FECD. Furthermore, these findings highlight the broader translational utility of FECD as a model for developing therapeutic strategies for rarer diseases similarly attributed to somatically unstable repeats. FUNDING: UK Research and Innovation, Moorfields Eye Charity, Fight for Sight, Medical Research Council, NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Grantová Agentura České Republiky, Univerzita Karlova v Praze, the National Brain Appeal's Innovation Fund and Rosetrees Trust.

• MeSH
• alely MeSH
• expanze trinukleotidových repetic MeSH
• Fuchsova endoteliální dystrofie * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mapování chromozomů MeSH
• nestabilita genomu MeSH
• orgánová specificita genetika   MeSH
• senioři MeSH
• transkripční faktor 4 * genetika   metabolismus   MeSH
• trinukleotidové repetice genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Corneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1, NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1, extending the phenotypic and genetic heterogeneity of inherited corneal disease.

• MeSH
• dědičné dystrofie rohovky * genetika   patologie   MeSH
• dekorin genetika   metabolismus   MeSH
• dospělí MeSH
• extracelulární matrix - proteiny * genetika   MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace * MeSH
• proteiny vázající vápník * genetika   MeSH
• rodokmen * MeSH
• senioři MeSH
• stroma rohovky patologie   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH