An online compendium of treatable genetic disorders

Abstract More than 4,000 genes have been associated with recognizable Mendelian/monogenic diseases. When faced with a new diagnosis of a rare genetic disorder, health care providers increasingly turn to internet resources for information to understand the disease and direct care. Unfortunately, it can be challenging to find information concerning treatment for rare diseases as key details are scattered across a number of authoritative websites and numerous journal articles. The website and associated mobile device application described in this article begin to address this challenge by providing a convenient, readily available starting point to find treatment information. The site, Rx-genes.com (https://www.rx-genes.com/), is focused on those conditions where the treatment is directed against the mechanism of the disease and thereby alters the natural history of the disease. The website currently contains 633 disease entries that include references to disease information and treatment guidance, a brief summary of treatments, the inheritance pattern, a disease frequency (if known), nonmolecular confirmatory testing (if available), and a link to experimental treatments. Existing entries are continuously updated, and new entries are added as novel treatments appear in the literature.

Orphanet (http://www.orphadata.org/cgi-bin/index.php, 10/09/2020) includes more than 7,800 disease-gene relationships. Each year about 250 rare genetic disease discoveries are added to the lists. These discoveries include pathogenic variants in a gene that had not previously been associated with disease and pathogenic variants in a gene previously associated with a different disease (Boycott et al., 2017).
While the diagnosis of genetic disorders has improved, management has not kept pace. For most genetic disorders, treatment is symptomatic and not directed against the mechanism of disease. For example, many genetic causes of deafness are effectively managed with cochlear implants, a therapy that is not specific to the underlying disorder (Usami, Nishio, Moteki, Miyagawa, & Yoshimura, 2020).
Brugada syndrome is managed with an implantable defibrillator, a therapy that is not directed against the underlying cardiac ion channel channelopathies (Brugada et al., 2016). Yet, for other disorders, such as phenylketonuria, treatment of individuals is directed at the underlying pathology and has a dramatic effect on the outcome (Jameson & Remmington, 2020).
When faced with a new diagnosis of a rare genetic disorder, physicians traditionally turned to textbooks and the medical literature for information to direct management. In recent years, however, the value of internet resources in patient care has been documented (Maggio, Aakre, Del Fiol, Shellum, & Cook, 2019). A number of online resources that detail the overall phenotype and management of genetic disorders are now available on a desktop computer or mobile device (OMIM, https://omim.org/; Orphanet, https://www.orpha.net/ consor/cgi-bin/index.php; GeneReviews, https://www.ncbi.nlm.nih. gov/books/NBK1116/; Clinical Genomic Database, https://research. nhgri.nih.gov/CGD/search/ (Solomon, Nguyen, Bear, & Wolfsberg, 2013); Genetic and Rare Disease Information Center, https:// rarediseases.info.nih.gov/; UpToDate, https://www.uptodate.com/ contents/search; ClinGen Actionability Knowledge Repository, https://actionability.clinicalgenome.org/ac/). When considering these disorders, providers pay particular attention to those with a specific treatment based on the underlying molecular pathology. In many instances, early identification, ideally before symptoms appear, leads to a superior outcome. The website described in this article is focused on those conditions where the treatment is directed against the mechanism of the disease and thereby alters the natural history of the disease in at least some of the patients.

| METHODS
All disorders selected for the website and associated mobile device application are Mendelian disorders associated with treatments that affect the underlying pathogenesis and progression of disease. The sources used to identify the genetic disorders include two publications (Lee et al., 2019;Milko et al., 2019), two websites (GeneReviews, https://www.ncbi.nlm.nih.gov/books/NBK1116/; Clinical Genomic Database, https://research.nhgri.nih.gov/CGD/ (Solomon et al., 2013)) and the table of contents from the last 2 years of 45 journals (Appendix S1) reviewed by one curator (DB) for titles that identified treatments of a genetic disorder.
Genetic disorders with a Food and Drug Administration (FDA) approved therapy were included in the website. Additionally, publications were reviewed by a single curator (DB) to evaluate therapies for other genetic disorders. If the article reported an improvement in more than one case the therapy was included in the approaches that a physician should consider.
Evidence of efficacy fell into two categories, those with published therapeutic guidelines, and those without a guideline. The latter were designated "expert opinion," Guidelines developed by a national society were preferred over those developed by disease specific foundations or expert panels. More recent guidelines were preferred over older guidelines. These were identified by a review of the literature and through web search engines.
The website and mobile device application provide a simple interface (Figure 1), allowing the user to submit a query based on any field in the database (Figure 2). Each entry is focused on a particular disease and contains a number of relevant data fields described in Table 1. Figure 3 is an example of an entry in the database. Information for every data field is not available for every disease. Some genes are associated with more than one disease.

| RESULTS
The database underlying the Rx-genes.com (https://www.rx-genes. F I G U R E 1 Homepage of Rx-genes.com (https://www.rx-genes. com/) website showing the search window that allows the user to perform a search in any field in the database F I G U R E 2 List of each of the fields in the database that can be queried at the Rx-genes.com (https://www.rx-genes.com/) website The diseases included in the database require a wide range of treatments due to the myriad physiologic pathways involved. For genes that share a physiologic pathway there is often a common disease process that is amenable to the same treatment or set of treatments.

| Dietary management
Dietary management plays an important role in 95 diseases. For example, limiting dietary galactose is effective for diseases arising from four genes that affect galactose metabolism (GALT, GALE, GALK1, and GALM).

| Hematopoietic stem cell transplantation
Based on the sources reviewed, hematopoietic stem cell transplantation (HSCT) has been reported to have been used effectively in 157 diseases. Most are disorders arising from dysfunction or failure of one or more stem cell lineages causing disorders such as severe combined immunodeficiency, thalassemia, and congenital amegakaryocytic thrombocytopenia. HSCT is also used to treat genetic abnormalities in CLCN7, TCIRG1, SNX10, and TNFRSF11A leading to osteopetrosis.
Additionally, HSCT has been used in a number of storage disorders (Krabbe disease, mucopolysaccharidosis (MPS) I, MPS II, MPS VII) as a way to supply the missing enzyme. T A B L E 1 Description of the data fields for each database entry underlying the Rx-genes.com (https://www.rx-genes.com/) website and mobile device application

Data field Data field description
Disease name Uses the disease name designation in OMIM where possible.
Gene name Uses the symbol assigned by the HUGO gene nomenclature Committee at the European Bioinformatics Institute (https://www.genenames.org/).

Current treatment
Lists treatment approaches that a physician should consider.
Evidence for treatment Indicates whether treatment is supported by a published guideline or relies on expert opinion.
Guideline reference 1 and guideline reference 2 Provides references when a disorder has published treatment guidelines.
Reference 1 and reference 2 Provides general information and treatment guidance for the genetic disorder.
ClinGen clinical actionability report Provides information and treatment guidance for the genetic disorder developed by ClinGen and found in the actionability knowledge repository (https://actionability.clinicalgenome.org/ac/) .

Inheritance
Uses AR for autosomal recessive, AD for autosomal dominant and XL for X-linked.
Disease frequency Provides an estimate of the disease prevalence. Where possible a birth prevalence is provided. When there is a range of prevalence figures an average of the highest and lowest values is used.
Genes included in disease frequency Contains the list of genes included in the disease frequency estimate.
Disease frequency reference 1 and disease frequency reference 2 Provides sources of the prevalence figures.
Is nonmolecular testing available to confirm a molecular diagnosis?
This is answered in the affirmative when the test involves a readily obtained sample such as blood, urine, cerebrospinal fluid, and bone marrow aspirate or involves a noninvasive procedure such as an MRI or ophthalmologic examination. Additionally, the test must be generally available. These tests are particularly important when the patient's phenotype combined with a molecular test that finds a variant of uncertain significance, do not provide enough information for a physician to make a treatment recommendation such as a hematopoietic stem cell transplant. Confirmatory tests performed in research laboratories and assays that require invasive procedures such as skin biopsy, liver biopsy, kidney biopsy, and brain biopsy are not considered as "available" tests as they require special procedures and handling and testing laboratories are not generally available.

| Solid organ transplantation
Solid organ transplantation is used to manage 18 disorders including liver transplantation for 12 disorders, kidney transplantation for 4 disorders, heart transplantation for 1 disorder, and thymus transplantation for 1 other disorder.

| Immunoglobulin therapy
Immunoglobulin therapy is used in the management of 42 immunodeficiencies in which agammaglobulinemia, hypogammaglobulinemia, or dysgammaglobulinemia are aspects of the diseases.

| Medications, vaccinations, and blood products
Medications, vaccinations, and blood products play a role in the management of 328 disorders. This includes 154 medications, 3 vaccines, and 9 different blood products (Appendix S2). While most medications are specific, some fall into a general category such as antibiotics.

| Gene therapy
Gene therapy is approved for four disorders: beta-thalassemia, spinal muscular atrophy, adenosine deaminase deficiency, and RPE65-related Leber congenital amaurosis.

| Uses of Rx-genes.com
Rx-genes.com (https://www.rx-genes.com/) is an initial effort targeted to clinicians in need of "just in time" information when they encounter a newly diagnosed patient in their office or in the hospital.
The website and associated mobile device application are focused on information that providers generally seek when faced with a newly For providers in the hospital setting, the need for "just in time" information delivered through decision support tools in the electronic medical records have been shown to improve patient care (Kwan et al., 2020). Links to the website through an application programming interface could be integrated into genetics decision support in the electronic medical record (https://www.sciencedirect.com/science/ article/pii/B9780128006818000141).

| Limitations
The website has a number of limitations: (a) Treatments published outside of the 45 English language journals, two articles and two websites reviewed will be missed. (b) Treatments found effective in small cohorts may not prove to be useful in a larger study of affected individuals, were not performed according to "good clinical practice"  (Dimmock, 2016). (e) At present the site only includes disorders with a treatment that is associated with the underlying pathogenesis. This is clearly a limited subset of "actionable" disorders that include a large number with anticipatory management guidelines and treatments unrelated to pathogenesis. (Milko et al., 2019;Cehyan-Birsoy et al., 2019;Reble et al., 2020;Adhikari et al., 2020;Richer & Laberge, 2019 (Katsoulakis et al., 2020;Mateo et al., 2018;Parikh, Love-Gregory, Duncavage, & Heusel, 2020). (h) Nonmolecular confirmatory testing was narrowly defined (Table 1) including only blood, urine, cerebrospinal fluid, or bone marrow aspirate as the sources of material for the test and noninvasive tests such as magnetic resonance imaging. It did not include skin punch biopsy, a commonly used sample type for numerous genetic tests. While skin biopsy is minimally invasive, its use is a particular problem in newborn screening where parents may be reluctant to agree to the procedure in an apparently healthy infant.

| Future considerations
Ongoing development of the website will focus first on disorders that have not been assessed for an associated nonmolecular confirmatory testing and the development of an application programming interface.
Early user feedback requested a link to all disease-gene associations, including those that are not treatable as defined by the website. Ongoing updates of the current catalogue of disorders and identification of new diseases to add to the site represent a special problem. It may be possible to employ a machine learning approach to find new entries and to ensure the site is kept up to date for the existing entries.

| Summary
Rx-genes.com (https://www.rx-genes.com/) represents an initial effort to provide a readily accessible website and mobile device application for clinicians seeking relevant "just-in-time" information from the medical literature when faced with an unfamiliar genetic diagnosis.
At present, the information is entirely focused on rare disorders where treatment is associated with the underlying pathogenesis of the disease. The site will update existing entries, add treatable disorders, and expand to include actionable disorders more broadly.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.