Delivering Telegenetics Services: Review and Synthesis of Best Practices.

Introduction: Before the COVID-19 public health emergency, few genetics providers used telehealth. As a response to this, many genetics providers began conducting telehealth care, referred to as telegenetics, usually with guidance from their institutions but without specific guidance related to the uniqueness of genetic services. Objectives: The Telegenetics Workgroup of the National Coordinating Center for Regional Genetics Networks convened a panel of experts in the fields of telemedicine, genetics, and genomics to review the existing literature on telegenetics and synthesize best operating practices for medical geneticists, genetic counselors, and metabolic dietitians providing telegenetics services. Methods: The group searched PubMed using the terms "telegenetics," "telemedicine + genetics," and "telehealth + genetics." The group also reviewed the Northeast Telehealth Resource Center's telegenetics webliography. Websites were searched, including the American Telemedicine Association's website, Center for Connected Health Policy, and National Telehealth Resource Center for position statements, standards documents, and guidelines. The group met frequently by videoconference and discussed the literature, and using expert consensus, the group determined best practices in providing telegenetics services. Results: These telegenetics best practices cover important aspects of telegenetics services, including, but not limited to, ongoing delivery of telegenetics services, use of special technology, legal and regulatory requirements, and considerations regarding special settings and circumstances in which telegenetics may be conducted. Conclusions: Recognizing the growing use of telegenetics and a future in which telegenetics continues to be part of the regular practice of genetics, this guide informs genetics providers of best practices for delivering telegenetics services to patients.

The DO-KB Knowledgebase: a 20-year journey developing the disease open science ecosystem.

In 2003, the Human Disease Ontology (DO, https://disease-ontology.org/) was established at Northwestern University. In the intervening 20 years, the DO has expanded to become a highly-utilized disease knowledge resource. Serving as the nomenclature and classification standard for human diseases, the DO provides a stable, etiology-based structure integrating mechanistic drivers of human disease. Over the past two decades the DO has grown from a collection of clinical vocabularies, into an expertly curated semantic resource of over 11300 common and rare diseases linking disease concepts through more than 37000 vocabulary cross mappings (v2023-08-08). Here, we introduce the recently launched DO Knowledgebase (DO-KB), which expands the DO's representation of the diseaseome and enhances the findability, accessibility, interoperability and reusability (FAIR) of disease data through a new SPARQL service and new Faceted Search Interface. The DO-KB is an integrated data system, built upon the DO's semantic disease knowledge backbone, with resources that expose and connect the DO's semantic knowledge with disease-related data across Open Linked Data resources. This update includes descriptions of efforts to assess the DO's global impact and improvements to data quality and content, with emphasis on changes in the last two years.

Modeling the enigma of complex disease etiology.

BACKGROUND: Complex diseases often present as a diagnosis riddle, further complicated by the combination of multiple phenotypes and diseases as features of other diseases. With the aim of enhancing the determination of key etiological factors, we developed and tested a complex disease model that encompasses diverse factors that in combination result in complex diseases. This model was developed to address the challenges of classifying complex diseases given the evolving nature of understanding of disease and interaction and contributions of genetic, environmental, and social factors. METHODS: Here we present a new approach for modeling complex diseases that integrates the multiple contributing genetic, epigenetic, environmental, host and social pathogenic effects causing disease. The model was developed to provide a guide for capturing diverse mechanisms of complex diseases. Assessment of disease drivers for asthma, diabetes and fetal alcohol syndrome tested the model. RESULTS: We provide a detailed rationale for a model representing the classification of complex disease using three test conditions of asthma, diabetes and fetal alcohol syndrome. Model assessment resulted in the reassessment of the three complex disease classifications and identified driving factors, thus improving the model. The model is robust and flexible to capture new information as the understanding of complex disease improves. CONCLUSIONS: The Human Disease Ontology's Complex Disease model offers a mechanism for defining more accurate disease classification as a tool for more precise clinical diagnosis. This broader representation of complex disease, therefore, has implications for clinicians and researchers who are tasked with creating evidence-based and consensus-based recommendations and for public health tracking of complex disease. The new model facilitates the comparison of etiological factors between complex, common and rare diseases and is available at the Human Disease Ontology website.

Interpretation challenge of small copy number variations in the imprinting regions.

We report the findings of small CNVs in two newborns in the genomic imprinting regions. They exemplified the challenge of interpreting small CNVs in diagnostic samples. Careful detection of small CNVs in the imprinting regions and effective genetic counseling are of clinical and reproductive significance.

Review of general and head and neck/oral and maxillofacial features of Charcot-Marie-Tooth disease and dental management considerations.

Charcot-Marie-Tooth disease (CMTD) is an uncommon progressive neuromuscular disorder of the peripheral nervous system and primarily leads to distal extremity weakness and sensory deficits. Frequently, affected patients manifest pes cavus, drop foot, and digit contractures that may pose significant challenges in ambulation and grasping objects. Although there are numerous articles of this syndrome in the medical literature, there is a limited number of dental publications. The objective of this article is to review the general and head and neck/oral and maxillofacial features of CMTD. General guidelines for dental management are also provided.

The Human Disease Ontology 2022 update.

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO's 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and genomic resources around the world. This update reports on the addition of 1,793 new disease terms, a 14% increase of textual definitions and the integration of 22 137 new SubClassOf axioms defining disease to disease connections representing the DO's complex disease classification. The DO's updated website provides multifaceted etiology searching, enhanced documentation and educational resources.

Gelatine-based drug-eluting bandage contact lenses: Effect of PEGDA concentration and manufacturing technique.

Drug-eluting bandage contact lenses (BCLs) have been widely studied as an alternative to eye drops due to their ability to increase the drug residence time and bioavailability as well as improve patient compliance. While silicone hydrogel polymers are commonly used in drug-eluting BCLs due to their transparency, mechanical properties and high oxygen permeability, gelatine hydrogels are also clear, flexible and have high oxygen permeability and may therefore be suitable contact lens materials. Moreover, the rheological properties of gelatine hydrogels allow their use as inks in extrusion-based 3D printers, therefore opening the door to a wide range of applications. Drug-loaded gelatine methacryloyl (GelMA) BCLs with different concentrations of poly (ethylene glycol) diacrylate (PEGDA) were prepared using solvent casting and 3D printing. The prepared lenses were characterised for their swelling ratio, in vitro degradation, and drug release properties. The results showed that the incorporation of 10% PEGDA improved the lenses' resistance to handling and protected them during degradation testing, reduced the swelling ratio and prolonged the release of dexamethasone (DEX). Both techniques were deemed suitable to use in the manufacturing of drug-eluting BCLs noting that the optimal formulation may vary according to the preparation technique utilised.

Challenges and opportunities for integrating genetic testing into a diagnostic workflow: heritable long QT syndrome as a model.

BACKGROUND: An increasing number of diagnostic evaluations incorporate genetic testing to facilitate accurate and timely diagnoses. The increasing number and complexity of genetic tests continue to pose challenges in deciding when to test, selecting the correct test(s), and using results to inform medical diagnoses, especially for medical professionals lacking genetic expertise. Careful consideration of a diagnostic workflow can be helpful in understanding the appropriate uses of genetic testing within a broader diagnostic workup. CONTENT: The diagnosis of long QT syndrome (LQTS), a life-threatening cardiac arrhythmia, provides an example for this approach. Electrocardiography is the preferred means for diagnosing LQTS but can be uninformative for some patients due to the variable presentation of the condition. Family history and genetic testing can augment physiological testing to inform a diagnosis and subsequent therapy. Clinical and laboratory professionals informed by peer- reviewed literature and professional recommendations constructed a generalized LQTS diagnostic workflow. This workflow served to explore decisions regarding the use of genetic testing for diagnosing LQTS. SUMMARY AND OUTLOOK: Understanding the complexities and approaches to integrating genetic testing into a broader diagnostic evaluation is anticipated to support appropriate test utilization, optimize diagnostic evaluation, and facilitate a multidisciplinary approach essential for achieving accurate and timely diagnoses.

Growth hormone as a rescue treatment in maple syrup urine disease with lessons from pediatric burn literature, case report and brief literature review.

Maple Syrup Urine Disease (MSUD) is a rare inherited disorder of branched chain amino acid metabolism characterized by cerebral edema and death in uncorrected metabolic crisis. It is conventionally treated with intensive nutritional therapy to prevent and correct metabolic crisis. This paper reports the use of growth hormone as a pharmacologic rescue agent in the case of an 11-year-old male with MSUD and metabolic crisis refractory to standard interventions. The initiation of short courses of growth hormone correlated with corrected mental status, resolution of metabolic acidosis, and improvement in plasma leucine levels on two occasions during an admission to the pediatric intensive care unit. This is the first known case report of the use of growth hormone in MSUD since contemporary dietary management became available. The discussion includes a literature review of the use of growth hormone in inherited diseases of amino acid metabolism and a brief discussion of protein anabolic pharmacotherapeutic agents shown to improve net protein balance in pediatric burn patients. We propose that growth hormone and other protein anabolic agents may be valuable adjuvants to standard therapy in children with inherited metabolic disease.

Duplication 6q24: More Than Just Diabetes.

Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.

Medical Foods for Inborn Errors of Metabolism: History, Current Status, and Critical Need.

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.

Stable transmission of complex chromosomal rearrangements involving chromosome 1q derived from constitutional chromoanagenesis.

BACKGROUND: Chromoanagenesis events encompassing chromoanasynthesis, chromoplexy, and chromothripsis are described in cancers and can result in highly complex chromosomal rearrangements derived from 'all-at-once' catastrophic cellular events. The complexity of these rearrangements and the original descriptions in cancer cells initially led to the assumption that it was an acquired anomaly. While rare, these phenomena involving chromosome 1 have been reported a few individuals in a constitutional setting. CASE PRESENTATION: Here, we describe a newborn baby who was initially referred for cytogenetic testing for multiple congenital anomalies including cystic encephalomalacia, patent ductus arteriosus, inguinal hernia, and bilateral undescended testicles. Chromosome analysis was performed and revealed a derivative chromosome 1 with an 1q24-q31 segment inserted into 1q42.13 resulting in gain of 1q24-q31. Whole genome SNP microarray analysis showed a complex pattern of copy number variants with four gains and one loss involving 1q24-q31. Mate pair next-generation sequencing analysis revealed 18 chromosome breakpoints, six gains along an 1q24-q31 segment, one deletion of 1q31.3 segment and one deletion of 1q42.13 segment, which is strongly evocative of a chromoanasynthesis event for developing this complex rearrangement. Parental chromosome analyses were performed and showed the same derivative chromosome 1 in the mother. CONCLUSIONS: To our knowledge, our case is the first case with familial constitutional chromoanagenesis involving chromosome 1q24-q42. This report emphasizes the value of performing microarray and mate pair next-generation sequencing analysis for individuals with germline abnormal or complex chromosome rearrangements.

Human Disease Ontology 2018 update: classification, content and workflow expansion.

The Human Disease Ontology (DO) (http://www.disease-ontology.org), database has undergone significant expansion in the past three years. The DO disease classification includes specific formal semantic rules to express meaningful disease models and has expanded from a single asserted classification to include multiple-inferred mechanistic disease classifications, thus providing novel perspectives on related diseases. Expansion of disease terms, alternative anatomy, cell type and genetic disease classifications and workflow automation highlight the updates for the DO since 2015. The enhanced breadth and depth of the DO's knowledgebase has expanded the DO's utility for exploring the multi-etiology of human disease, thus improving the capture and communication of health-related data across biomedical databases, bioinformatics tools, genomic and cancer resources and demonstrated by a 6.6× growth in DO's user community since 2015. The DO's continual integration of human disease knowledge, evidenced by the more than 200 SVN/GitHub releases/revisions, since previously reported in our DO 2015 NAR paper, includes the addition of 2650 new disease terms, a 30% increase of textual definitions, and an expanding suite of disease classification hierarchies constructed through defined logical axioms.

The Sheep Cornea: Structural and Clinical Characteristics.

PURPOSE: The aim of this study was to perform qualitative and quantitative analyses to characterize the corneas of young, healthy sheep. MATERIALS AND METHODS: Eight healthy male sheep, 10 months to 1 year of age, were included as experimental subjects. Central corneal thickness was measured using a handheld pachymeter, and an Easygraph corneal topographer provided topographic maps. Microstructural imaging of corneal layers was achieved by using the Heidelberg Retina Tomograph III Rostock Corneal Module in vivo corneal microscope (IVCM). An Ocular Response Analyzer (ORA) provided quantitative measurements of intraocular pressure (IOP), corneal hysteresis (CH), and corneal resistance factor. Tissue histology and immunohistochemistry were carried out to obtain detail on the corneal layers. RESULTS: Light microscopy and immunohistochemical labeling revealed a stratified epithelium, a limbus with numerous limbal crypts, a thick basement membrane, a thin Bowman's layer, a thick corneal stroma with a dense population of keratocytes, and a thick, hyper-reflective Descemet's membrane. Using IVCM, the cell density of the basal layer was noted to be significantly higher than that of other epithelial cell types. The density of keratocytes was significantly higher (P value = 0.0223) in the anterior compared to the posterior stroma. The endothelial cells were organized in a characteristic honeycomb pattern. The mean and standard deviation values for central corneal pachymetry were 623.14 ± 19.5 µm and 616.37 ± 34.87 µm for the left and right eyes, respectively. ORA-derived mean values for IOPcc and CH for the left and right eyes were 14.93 ± 1.73 mm Hg and 15.16 ± 2.02 mm Hg and 3.56 ± 0.72 mm Hg and 3.73 ± 0.49 mm Hg, respectively. CONCLUSIONS: The anatomical and clinical characteristics of the sheep cornea, as outlined in this study, make the sheep a suitable and relevant model for corneal research. This study provides researchers with important data on the suitability of sheep as a model for ophthalmic experiments.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Wound healing in the eye: Therapeutic prospects.

In order to maintain a smooth optical surface the corneal epithelium has to continuously renew itself so as to maintain its function as a barrier to fluctuating external surroundings and various environmental insults. After trauma, the cornea typically re-epithelializes promptly thereby minimizing the risk of infection, opacification or perforation. A persistent epithelial defect (PED) is usually referred to as a non-healing epithelial lesion after approximately two weeks of treatment with standard therapies to no avail. They occur following exposure to toxic agents, mechanical injury, and ocular surface infections and are associated with significant clinical morbidity in patients, resulting in discomfort or visual loss. In the case of deeper corneal injury and corneal pathology the wound healing cascade can also extend to the corneal stroma, the layer below the epithelium. Although significant progress has been made in recent years, pharmaco-therapeutic agents that promote corneal healing remain limited. This article serves as a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments into ocular wound healing.

Medicated ocular bandages and corneal health: potential excipients and active pharmaceutical ingredients.

Corneal blindness can occur due to improper healing of the corneal tissues after induced injury or abrasion which can be accidental, pathogenic, or after corneal surgery. Abnormal regulation of the healing mechanisms can lead to corneal opacity. Reducing inflammation and promoting epithelial wound healing are crucial for scar-free corneal recovery without eyesight complications. Current approaches for corneal wound healing involve amniotic membrane (AM) bandages, bandage contact lenses (BCL), and collagen shields in conjunction with frequent administration of therapeutic eye drops. The problem with eye drops is poor bioavailability and patient incompliance that might lead to corneal wound healing complications and poor clinical outcomes. Various methods have been proposed for loading drugs into medicated bandage lenses. There are advantages and limitations associated with each technique regarding the ease of manufacture, drug loading, release kinetics, and suitability with various therapeutics and hydrogel types. There is still, however, no drug-eluting corneal bandage on the market despite the need for such a convenient and cost-efficient strategy for corneal wound healing. This review will highlight materials and therapeutics that can be used in medicated ocular bandages and various ways of incorporating drugs, while discussing the limitations and challenges associated with bringing medicated ocular bandages in the market.

Aberrant Patterns of Key Epithelial Basement Membrane Components in Keratoconus.

PURPOSE: In the cornea, the epithelial basement membrane (BM) plays an important role in maintaining corneal integrity and homeostasis. Aberrations in this vital structure are associated with several corneal pathologies including keratoconus. The aim of this study was to investigate the expression of key structural components of the epithelial BM in keratoconic corneas and to identify and describe any aberrant patterns. METHODS: Immunohistochemical labeling of key BM components including fibronectin, laminin, and type IV and VII collagen was performed in healthy and keratoconic corneas. RESULTS: Clear changes in the BM components in the keratoconic corneas were seen with the key structural components either being absent or forming a discontinuous pattern. Another aberrant pattern, the expression of BM proteins, particularly fibronectin, laminin, and type IV collagen, in the anterior stroma of keratoconic corneas was also observed. CONCLUSIONS: These results indicate the activation of keratocytes into the fibroblast and myofibroblast wound phenotypes and the potential source of corneal scarring commonly observed in keratoconic corneas. Our data also support the hypothesis of dysregulated collagen synthesis and breakdown in the keratoconic cornea, in particular, the BM, and suggest a role for the BM in initiation and progression of keratoconus.

Solid Organ Transplant-Transmitted Tuberculosis Linked to a Community Outbreak - California, 2015.

In the spring of 2015, a local health department (LHD) in county A notified the California Department of Public Health (CDPH) about three adults with close ties to one another and a congregate community site who had received diagnoses of tuberculosis (TB) disease within a 3-month period. Subsequent review revealed matching TB genotypes indicating that the cases were likely part of a chain of TB transmission. Only three TB cases in California in the preceding 2 years shared this same genotype. One of those three previous cases occurred in a lung-transplant recipient who had no identified epidemiologic links to the outbreak. CDPH, multiple LHDs, and CDC conducted an investigation and determined that the lung-transplant donor (patient 1) was epidemiologically linked to the three outbreak cases and had a tuberculin skin test (TST) conversion detected in 2012 upon reentry at a local jail. Three other solid organ recipients from this donor were identified; none had developed TB disease. This investigation suggests that review of organ donors' medical records from high-risk environments, such as jails, might reveal additional information about TB risk. The evaluation of TB in organ recipients could include genotyping analysis (1) and coordination among local, state, and national partners to evaluate the potential for donor-derived TB.

Keratocytes are induced to produce collagen type II: A new strategy for in vivo corneal matrix regeneration.

The stroma, the middle layer of the cornea, is a connective tissue making up most of the corneal thickness. The stromal extracellular matrix (ECM) consists of highly organised lamellae which are made up of tightly packed fibrils primarily composed of collagens type I and V. This layer is interspersed with keratocytes, mesenchymal cells of neural crest origin. We have previously shown that adult corneal keratocytes exhibit phenotypic plasticity and can be induced into a neuronal phenotype. In the current study we evaluated the potential of keratocytes to produce collagen type II via phenotypic reprogramming with exogenous chondrogenic factors. The cornea presents a challenge to tissue engineers owing to its high level of organisation and the phenotypic instability of keratocytes. Traditional approaches based on a scar model do not support the engineering of functional stromal tissue. Type II collagen is not found in the adult cornea but is reported to be expressed during corneal development, raising the possibility of using such an approach to regenerate the corneal ECM. Keratocytes in culture and within intact normal and diseased tissue were induced to produce collagen type II upon treatment with transforming growth factor Beta3 (TGFß3) and dexamethasone. In vivo treatment of rat corneas also resulted in collagen type II deposition and a threefold increase in corneal hardness and elasticity. Furthermore, the treatment of corneas and subsequent deposition of collagen type II did not cause opacity, fibrosis or scarring. The induction of keratocytes with specific exogenous factors and resulting deposition of type II collagen in the stroma can potentially be controlled by withdrawal of the factors. This might be a promising new approach for in vivo corneal regeneration strategies aimed at increasing corneal integrity in diseases associated with weakened ectatic corneal tissue such as keratoconus.