Lived experiences of genetic diagnosis for rare disease patients: a qualitative interview study.

BACKGROUND: Genetic diagnosis is often understood as a single event within the care pathway of rare disease patients. Legal, policy and ethical scholarship focusing on rare diseases and genetic information discusses questions of how to best deal with the process of genetic diagnosis and the communication of genetic information within a given health system. We co-created a research design with rare disease patients and their families in Austria to explore in-depth the experiences of genetic diagnosis for people affected by rare diseases. Our objective was to trace the whole pathway of genetic testing and understand how rare disease patients experience genetic diagnosis as part of their care pathway in the healthcare system. RESULTS: Data was collected through in-depth semi-structured qualitative interviews with 14 patients with a suspected or diagnosed rare disease or their parents, focusing on their perception of the pathway of genetic diagnosis in Austria. This pathway included the initial triggering of genetic diagnosis, the process of testing and its immediate (communication of results, counselling) and long-term, wider aftermath. Patients missed a clear link to already established forms of care such as their primary care/treating physicians. They also advocate for an integrated and interdisciplinary care pathway. CONCLUSIONS: Our study underscores the importance of a continuous care and communication pathway spanning from the initial genetic diagnosis process to post-test phases. It further shows the importance of exploring patients' perspectives through qualitative research methods to understand the intricate workings of public health policies and tools. Integrating genetic diagnosis into a broader care trajectory is crucial for a holistic approach to care for rare disease patients who often rely on regular interactions with the healthcare system. Achieving this holistic approach requires collaboration between experts in specific rare disease areas, primary care physicians, and support networks.

Towards personalized genome-scale modeling of inborn errors of metabolism for systems medicine applications.

Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.

Availability of Genetic Tests in Public Health Services in Brazil: Data from the Brazilian Rare Diseases Network.

INTRODUCTION: The Brazilian Policy for Comprehensive Care for People with Rare Diseases (BPCCPRD) was published in 2014, accrediting several reference centers and incorporating many genetic tests for the diagnosis of rare diseases (RDs). The Brazilian Network of Rare Diseases (RARAS) comprises more than 40 institutions that offer diagnosis and treatment for RDs in Brazil. This network includes Reference Services for Rare Diseases (RDRS), Reference Services for Newborn Screening (NSRS), and University Hospitals distributed in all Brazilian regions. OBJECTIVE: The aim of the study was to map the availability and distribution of the BPCCPRD diagnostic procedures in the Brazilian Unified Health System through RARAS. METHOD: Data were collected through a questionnaire on the Research Electronic Data Capture platform, with 22 questions regarding the availability of procedures. Thirty-seven coordinators from RARAS participating centers received the questionnaire link for participation by email from August/2020 to March/2021. All participating institutions ethically approved this project. RESULTS: Of the 37 institutions, 23 (62.16%) offered cytogenetic tests, 20 (54.05%) offered molecular procedures, and 22 (59.46%) offered inborn errors of metabolism diagnostic tests. The Southern blot analysis, enzyme assays on cultured tissue and urinary organic acid tests had the highest outsourcing rate. On the other hand, the procedures most frequently performed on-site were bone marrow karyotype and long-term cultured karyotype. It was observed that 10 of the 37 centers (27%) did not provide access to investigated procedures (on-site or outsourced). The North and Midwest regions stood out in terms of the unavailability of such techniques in at least 40% of the evaluated institutions. DISCUSSION AND CONCLUSION: This study reveals large discrepancies in the supply of diagnostic procedures in the Brazilian territory. Moreover, there is a broad collaboration between services through the outsourcing of multiple diagnostic techniques to address this issue. Finally, this work corroborates the importance of mapping services for the diagnosis and treatment of individuals with RDs to propose actions for the better supply and distribution of these procedures.

Children with a rare congenital genetic disorder: a systematic review of parent experiences.

BACKGROUND: Caring for a child with a chronic disease may be demanding and stressful. When a child has a rare condition, the impact of care on parents is amplified due to the rarity of the diagnosis. In order to address the lack of generalized and synthesized knowledge regarding parents' experiences of having a child with a rare genetic disorder, and give a holistic picture of these experiences, a systematic review of the available qualitative research was conducted. METHODS: We performed a systematic review, including qualitative studies on parents of children with rare genetic disorders, published between 2000 and 2020. RESULTS: The review included 33 qualitative studies. Findings were synthesized and categorized according to three main themes: Parents' experiences with health care, Responsibilities and challenges, and Factors promoting positive experiences in parents. The findings demonstrate that parents of children with rare genetic disorders share many common challenges, despite evident differences across conditions. CONCLUSION: Coordinated care, and a more holistic approach in the follow up of children with rare genetic disorders is needed. International collaboration on research, diagnostics, producing scientific correct and understandable information available for health care professionals and lay people should be prioritized.

Epidemiology of rare diseases in Brazil: protocol of the Brazilian Rare Diseases Network (RARAS-BRDN).

The Brazilian Policy of Comprehensive Care for People with Rare Diseases (BPCCPRD) was established by the Ministry of Health to reduce morbidity and mortality and improve the quality of life of people with rare diseases (RD). Several laboratory tests, most using molecular genetic technologies, have been incorporated by the Brazilian Public Health System, and 18 specialised centres have so far been established at university hospitals (UH) in the capitals of the Southern, Southeastern and Northeastern regions. However, whether the available human and technological resources in these services are appropriate and sufficient to achieve the goals of care established by the BPCCPRD is unknown. Despite great advances in diagnosis, especially due to new technologies and the recent structuring of clinical assessment of RD in Brazil, epidemiological data are lacking and when available, restricted to specific disorders. This position paper summarises the performance of a nationally representative survey on epidemiology, clinical status, and diagnostic and therapeutic resources employed for individuals with genetic and non-genetic RD in Brazil. The Brazilian Rare Disease Network (BRDN) is under development, comprising 40 institutions, including 18 UH, 17 Rare Diseases Reference Services and five Newborn Screening Reference Services. A retrospective study will be initially conducted, followed by a prospective study. The data collection instrument will use a standard protocol with sociodemographic data and clinical and diagnostic aspects according to international ontology. This great collaborative network is the first initiative of a large epidemiological data collection of RD in Latin America, and the results will increase the knowledge of RD in Brazil and help health managers to improve national public policy on RD in Brazil.

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis.

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

New problems of a new health system: the creation of a national public policy of rare diseases care in Brazil (1990s-2010s). / Nuevos problemas de un nuevo sistema de salud: la creación de una política pública nacional de atención de enfermedades raras en Brasil (1990-2014).

This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.

En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.

The Genomic Medicine Integrative Research Framework: A Conceptual Framework for Conducting Genomic Medicine Research.

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.

Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

Integrated Genomic Medicine: A Paradigm for Rare Diseases and Beyond.

Individualized medicine, or the tailoring of therapeutic interventions to a patient's unique genetic, biochemical, physiological, exposure and behavioral profile, has been enhanced, if not enabled, by modern biomedical technologies such as high-throughput DNA sequencing platforms, induced pluripotent stem cell assays, biomarker discovery protocols, imaging modalities, and wireless monitoring devices. Despite successes in the isolated use of these technologies, however, it is arguable that their combined and integrated use in focused studies of individual patients is the best way to not only tailor interventions for those patients, but also shed light on treatment strategies for patients with similar conditions. This is particularly true for individuals with rare diseases since, by definition, they will require study without recourse to other individuals, or at least without recourse to many other individuals. Such integration and focus will require new biomedical scientific paradigms and infrastructure, including the creation of databases harboring study results, the formation of dedicated multidisciplinary research teams and new training programs. We consider the motivation and potential for such integration, point out areas in need of improvement, and argue for greater emphasis on improving patient health via technological innovations, not merely improving the technologies themselves. We also argue that the paradigm described can, in theory, be extended to the study of individuals with more common diseases.

Proceedings of the 2016 Santa Fe Bone Symposium: New Concepts in the Management of Osteoporosis and Metabolic Bone Diseases.

The Santa Fe Bone Symposium is an annual meeting of healthcare professionals and clinical researchers that details the clinical relevance of advances in knowledge of skeletal diseases. The 17th Santa Fe Bone Symposium was held in Santa Fe, New Mexico, USA, on August 5-6, 2016. The program included plenary lectures, oral presentations by endocrinology fellows, meet-the-professor sessions, and panel discussions, all aimed to provide ample opportunity for interactive discussions among all participants. Symposium topics included recent developments in the translation of basic bone science to patient care, new clinical practice guidelines for postmenopausal osteoporosis, management of patients with disorders of phosphate metabolism, new and emerging treatments for rare bone diseases, strategies to enhance fracture healing, and an update on Bone Health Extension for Community Healthcare Outcomes, using a teleconferencing platform to elevate the level of knowledge of healthcare professionals in underserved communities to deliver best practice care for skeletal diseases. The highlights and important clinical messages of the 2016 Santa Fe Bone Symposium are provided herein by each of the faculty presenters.

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Structural and functional analogies and differences between histidine decarboxylase and aromatic l-amino acid decarboxylase molecular networks: Biomedical implications.

Human histidine decarboxylase (HDC) and dopa decarboxilase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively. The enzymes share many structural and functional analogies, while their product metabolisms also follow similar patterns that are confluent in some metabolic steps. They are involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation. As a consequence, metabolic elements of both BA subfamilies are also co-participants in a long list of human diseases. This review summarizes the analogies and differences in their origin (HDC and DDC) as well as their common pathophysiological scenarios. The major gaps of information are also underlined, as they delay the possibility of holistic approaches that would help personalized medicine and pharmacological initiatives for prevalent and rare diseases.

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.

BACKGROUND: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. METHODS: We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient's tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. RESULTS: WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. CONCLUSIONS: This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.

Hypermanganesemia with Dystonia, Polycythemia and Cirrhosis (HMDPC) due to mutation in the SLC30A10 gene.

Manganese (Mn) is an essential element for metabolic pathways but it can be toxic when present in excessive amounts in the body. Hypermanganesemia along with dystonia, polycythemia, characteristic MRI brain findings in the basal ganglia, and chronic liver disease are the hallmarks of an inherited Mn transporter defect due to mutations in the SLC30A10 gene. We are reporting three siblings who presented with features of dystonia, polycythemia, MRI brain showing basal ganglia hyperintensity on T1 weighted images and chronic liver disease. Blood Mn levels were markedly elevated in the affected patients. Mutation analysis of DNA samples of the affected children confirmed a homozygous missense mutation in SLC30A10. Chelation therapy with intravenous disodium calcium edetate was started in two siblings and led to a marked decrease in whole blood Mn. Oral Penicillamine was later added to the therapy which further improved blood Mn levels. This is a rare disorder and is one of the potentially treatable inherited metal storage disorders. It can be fatal if left untreated. Penicillamine may be an effective alternative to disodium calcium edetate.

Cultural differences define diagnosis and genomic medicine practice: implications for undiagnosed diseases program in China.

Despite the current acceleration and increasing leadership of Chinese genetics research, genetics and its clinical application have largely been imported to China from the Occident. Neither genetics nor the scientific reductionism underpinning its clinical application is integral to the traditional Chinese worldview. Given that disease concepts and their incumbent diagnoses are historically derived and culturally meaningful, we hypothesize that the cultural expectations of genetic diagnoses and medical genetics practice differ between the Occident and China. Specifically, we suggest that an undiagnosed diseases program in China will differ from the recently established Undiagnosed Diseases Program at the United States National Institutes of Health; a culturally sensitive concept will integrate traditional Chinese understanding of disease with the scientific reductionism of Occidental medicine.