Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

Intraocular pressure before and after capsulorhexis using two viscoelastic substances and two surgical approaches in enucleated porcine eyes.

AIM: To investigate the influence of ophthalmic viscoelastic devices (OVDs) and different surgical approaches on the intraocular pressure (IOP) before and after creation of the curvilinear circular capsulorhexis (CCC) as a measure for anterior chamber stability during this maneuver. METHODS: Prospective experimental WetLab study carried out on enucleated porcine eyes. IOP was measured before and after CCC with the iCare Rebound tonometer (iCare ic200; iCare Finland Oy, Vantaa, Finland). The OVDs used were a cohesive one [Z-Hyalin, Carl Zeiss Meditec AG, Germany; hyaluronic acid (HA)] and a dispersive [Z-Celcoat, Carl Zeiss Meditec AG, Germany; hydroxy propylmethylcellulosis (HPMC)]. The CCC was created using Utrata forceps or 23 g microforceps in different combinations with the OVDs. RESULTS: Using the Utrata forceps the IOP dropped from 63.65±6.44 to 11.25±3.63 mm Hg during the CCC. The use of different OVDs made no difference. Using the 23 g microforceps the IOP dropped from 65.35±8.15 to 36.55±6.09 mm Hg. The difference between IOP drop using either Utrata forceps or 23 g microforceps was highly significant regardless of the OVD used. CONCLUSION: Using the sideport for the creation of the capsulorhexis leads to a lesser drop in IOP during this maneuver compared to the main incision in enucleated porcine eyes. The use of different OVD has no significant influence on IOP drop.

A corpus of GA4GH Phenopackets: case-level phenotyping for genomic diagnostics and discovery.

The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present phenopacket-store. Version 0.1.12 of phenopacket-store includes 4916 phenopackets representing 277 Mendelian and chromosomal diseases associated with 236 genes, and 2872 unique pathogenic alleles curated from 605 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.

Phenopacket-tools: Building and validating GA4GH Phenopackets.

The Global Alliance for Genomics and Health (GA4GH) is a standards-setting organization that is developing a suite of coordinated standards for genomics. The GA4GH Phenopacket Schema is a standard for sharing disease and phenotype information that characterizes an individual person or biosample. The Phenopacket Schema is flexible and can represent clinical data for any kind of human disease including rare disease, complex disease, and cancer. It also allows consortia or databases to apply additional constraints to ensure uniform data collection for specific goals. We present phenopacket-tools, an open-source Java library and command-line application for construction, conversion, and validation of phenopackets. Phenopacket-tools simplifies construction of phenopackets by providing concise builders, programmatic shortcuts, and predefined building blocks (ontology classes) for concepts such as anatomical organs, age of onset, biospecimen type, and clinical modifiers. Phenopacket-tools can be used to validate the syntax and semantics of phenopackets as well as to assess adherence to additional user-defined requirements. The documentation includes examples showing how to use the Java library and the command-line tool to create and validate phenopackets. We demonstrate how to create, convert, and validate phenopackets using the library or the command-line application. Source code, API documentation, comprehensive user guide and a tutorial can be found at https://github.com/phenopackets/phenopacket-tools. The library can be installed from the public Maven Central artifact repository and the application is available as a standalone archive. The phenopacket-tools library helps developers implement and standardize the collection and exchange of phenotypic and other clinical data for use in phenotype-driven genomic diagnostics, translational research, and precision medicine applications.

GA4GH Phenopackets: A Practical Introduction.

The Global Alliance for Genomics and Health (GA4GH) is developing a suite of coordinated standards for genomics for healthcare. The Phenopacket is a new GA4GH standard for sharing disease and phenotype information that characterizes an individual person, linking that individual to detailed phenotypic descriptions, genetic information, diagnoses, and treatments. A detailed example is presented that illustrates how to use the schema to represent the clinical course of a patient with retinoblastoma, including demographic information, the clinical diagnosis, phenotypic features and clinical measurements, an examination of the extirpated tumor, therapies, and the results of genomic analysis. The Phenopacket Schema, together with other GA4GH data and technical standards, will enable data exchange and provide a foundation for the computational analysis of disease and phenotype information to improve our ability to diagnose and conduct research on all types of disorders, including cancer and rare diseases.

The Medical Action Ontology: A Tool for Annotating and Analyzing Treatments and Clinical Management of Human Disease.

Navigating the vast landscape of clinical literature to find optimal treatments and management strategies can be a challenging task, especially for rare diseases. To address this task, we introduce the Medical Action Ontology (MAxO), the first ontology specifically designed to organize medical procedures, therapies, and interventions in a structured way. Currently, MAxO contains 1757 medical action terms added through a combination of manual and semi-automated processes. MAxO was developed with logical structures that make it compatible with several other ontologies within the Open Biological and Biomedical Ontologies (OBO) Foundry. These cover a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. We have created a database of over 16000 annotations that describe diagnostic modalities for specific phenotypic abnormalities as defined by the Human Phenotype Ontology (HPO). Additionally, 413 annotations are provided for medical actions for 189 rare diseases. We have developed a web application called POET (https://poet.jax.org/) for the community to use to contribute MAxO annotations. MAxO provides a computational representation of treatments and other actions taken for the clinical management of patients. The development of MAxO is closely coupled to the Mondo Disease Ontology (Mondo) and the Human Phenotype Ontology (HPO) and expands the scope of our computational modeling of diseases and phenotypic features to include diagnostics and therapeutic actions. MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions. METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology. FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases. CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO). FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.

[Combined retinal vascular occlusion after overexertion in sport at a young age : An unusual case as interdisciplinary challenge]. / Kombinierter Netzhautgefäßverschluss nach sportlicher Überanstrengung im jungen Alter : Ein ungewöhnlicher Fall als interdisziplinäre Herausforderung.

This case report presents a unilateral visual impairment after overexertion in sport at a young age. A combined central retinal vein occlusion with a cilioretinal arterial branch occlusion was diagnosed. This clinical picture has been described in case series and does not usually have an embolic etiology. In the cardiovascular clarification a patent foramen ovale was found, which was surgically closed.

Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches.

Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch's membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularisations, of the skin including soft, ivory-colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. There is yet no definitive therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. Very recently, the ABCC6 gene on chromosome 16p13.1 was found to be associated with the disease. Mutations within ABCC6 cause reduced or absent transmembraneous transport that leads to accumulation of extracellular material. Presumably, this mechanism causes calcification of elastic fibers. Despite the characteristic clinical features, the variability in phenotypic expressions, and the low prevalence may be responsible for the disease being underdiagnosed. This review compiles and summarizes current knowledge of PXE pathogenesis and clinical findings. Furthermore, different therapeutic strategies to treat retinal manifestations are discussed, including thermal laser coagulation, photodynamic therapy, and intravitreal injections of drugs inhibiting vascular endothelial growth factor.

Combined intravitreal bevacizumab and photodynamic therapy for neovascular age-related macular degeneration.

BACKGROUND: Our aim was to evaluate the short-term safety and efficacy of combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in neovascular age-related macular degeneration (AMD). METHODS: A prospective non-randomized interventional case series of 30 eyes of 30 patients with choroidal neovascularization (CNV) caused by AMD was studied. All patients were treated with PDT followed by an intravitreal injection of bevacizumab (1.5 mg) on the same day. Ophthalmic evaluations included determination of best-corrected visual acuity by using ETDRS charts. CNV lesion characteristics were determined by fluorescein angiography, and retinal morphology by optical coherence tomography. Review examinations were performed 1, 4, and 12 weeks following treatment. RESULTS: The median ETDRS letter scores increased by 3 letters after 4 weeks and 4.3 letters after 12 weeks. Median central retinal thickness decreased from the baseline by 145 microm (week 1), 205 microm (week 4), and 171 microm (week 12), respectively (P < 0.0001, for all comparisons). One patient experienced a transient moderate vision loss after 4 weeks post treatment. Leakage on fluorescein angiography was resolved in all patients at week 12. No significant ocular or systemic side-effects were observed. CONCLUSIONS: Short-term results suggest that a single PDT in combination with intravitreal bevacizumab is safe and associated with stabilization of visual acuity and decrease of intraretinal and subretinal fluid accumulation in the macula. Further evaluation of this treatment strategy for neovascular AMD appears warranted.