One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency.

BACKGROUND: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. OBJECTIVE: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. METHODS: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. RESULTS: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. CONCLUSIONS: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients

Nosology of genetic skeletal disorders: 2023 revision

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine

PEDIA: prioritization of exome data by image analysis.

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis

Impact of the COVID-19 pandemic on health care and daily life of patients with rare diseases from the perspective of patient organizations – a qualitative interview study

Abstract Background During the COVID-19 pandemic people affected by rare diseases (RD) or caregiver of affected children have faced additional challenges. The pandemic has affected physical and mental health, social life and has led to financial consequences. Our objectives were to identify the impact of COVID-19 (1) on health care and (2) on daily life and participation of patients with RDs or caregivers from the perspective of representatives of patient organizations. Moreover, we explored their perspective on experiences of pandemic stress and resources during the pandemic. Results We conducted 18 semi-structured interviews with representatives of patient organizations (e.g. chairperson, members of the steering committee), who were asked about the experiences of their members. The interviews were transcribed verbatim and analyzed using the framework approach. We contextualized our findings on the basis of the International Classification of Functioning, Disability and Health (ICF) model and adapted it according to identified subthemes. Patients and caregivers were confronted with aspects of pandemic stress such as lack of information, access and information regarding vaccination and being a risk group for COVID-19 infection. Physical and mental functioning was reported to be negatively impacted. Lock downs and contact restrictions led, e.g., to increasing lack of nursing services or lack of necessary informal support. Participation e.g. in social life and work was reduced. Health care services including medical care and supportive care as well as additional therapies were disrupted and greater effort was necessary to organize care. According to participants, central resources were informal support networks, digitalization, patient organizations and individual characteristics. Conclusions Our study highlights the consequences of the COVID-19 pandemic on the situation of people affected by RDs and caregivers. Contextualization of the results into the biopsychosocial model reinforces the impact of the pandemic on health care as well as daily life and participation. Major challenges and difficulties were experienced during lockdowns and contact restrictions. Depending on the risk of an infection with COVID-19, certain patient groups were still isolated and reduced social contacts or still followed strict hygienic measures (e.g., wearing medical masks). Future pandemic control measures, e.g. on lockdowns and closing facilities, should consider the challenges of people with RDs and caregivers of affected children

se-atlas.de - medical care atlas for people with rare diseases

Eine Erkrankung zählt in der Europäischen Union zu den Seltenen Erkrankungen (SE), wenn diese nicht mehr als 5 von 10.000 Menschen betrifft. Derzeit existiert mit mehr als 6000 SE eine sowohl große als auch heterogene Menge an unterschiedlichen Krankheitsbilder, die in ihrer Symptomatik komplex, vielschichtig und damit im medizinischen Alltag schwierig einzuordnen sind. Dies erschwert Diagnosefindung und Behandlung sowie das Auffinden eines passenden Ansprechpartners, da es nur wenige Experten für jede einzelne SE gibt. Der medizinische Versorgungsatlas für Seltene Erkrankungen www.se-atlas.de ermöglicht anhand von Erkrankungsnamen die Suche nach Versorgungseinrichtungen und Selbsthilfeorganisationen zu bestimmten SE und stellt die Suchergebnisse geografisch dar. Ebenso gibt er einen Überblick über alle deutschen Zentren für SE, die eine Anlaufstelle für betroffene Personen mit unklarer Diagnose darstellen. Der se-atlas dient als Kompass durch die heterogene Menge an Informationen über Versorgungseinrichtungen für SE und stellt niederschwellig Informationen für eine breite Nutzergruppe von Betroffenen bis hin zu Mitgliedern des medizinischen Versorgungsteams bereit.In the European Union a disease is classified as rare if it affects no more than 5 out of 10,000 people. Currently, there are more than 6000 rare diseases, consisting of a large and heterogeneous number of different diseases that are complex in their symptomatology, multidimensional and therefore difficult to classify in everyday medical practice. This complicates the diagnosis and treatment as well as finding a suitable contact person, as there are only a few experts for each individual rare disease. The medical care atlas for rare diseases www.se-atlas.de enables the search for care facilities and patient organizations for specific rare diseases by disease name and presents the search results geographically. It also provides an overview of all German centers for rare diseases, which are a contact point for patients with an unclear diagnosis. The se-atlas serves as a compass through the heterogeneous amount of information on care facilities for rare diseases and provides low-threshold information for a broad user group, from affected persons to members of the medical care team

Ein strukturierter Versorgungspfad von der Pädiatrie in die Erwachsenenmedizin für Jugendliche und junge Erwachsene mit einer seltenen Erkrankung

<jats:title>Zusammenfassung</jats:title><jats:p>Die erfolgreiche Organisation und Umsetzung des Übergangs von Jugendlichen und jungen Erwachsenen mit einer chronischen seltenen Erkrankung aus der Pädiatrie in eine Versorgungsform (Transition) und Versorgungsstruktur (Transfer) der Erwachsenenmedizin ist eine wichtige Aufgabe im dezentral aufgebauten deutschen Gesundheitssystem. Ein mittlerweile in der Praxis erprobtes Programm stellt der strukturierte Versorgungspfad des vom Innovationsfonds des gemeinsamen Bundesausschuss (G‑BA) geförderten Konsortiums TRANSLATE-NAMSE dar (Förderkennzeichen 01NVF16024 TRANSLATE-NAMSE). Grundlage des Übergangs in diesem Programm ist der qualitätsgesicherte Informations- und Kompetenztransfer vom pädiatrischen Behandlungsteam zum adoleszenten Patienten, sowie zur neuen Versorgungseinrichtung. Basierend auf einer strukturierten Epikrise und Erhebung des individuellen Beratungsbedarfs erfolgt, ab dem Alter von 16 Jahren, die strukturierte Transitionsschulung des Patienten durch den Pädiater. Nach erfolgreich absolvierten Transfersprechstunden, gemeinsam mit Vertretern der bisherigen pädiatrischen und der zukünftigen erwachsenenmedizinischen Versorgungseinrichtungen, mündet der Prozess in die Übergabe aller notwendigen medizinischen Unterlagen an den Patienten und den Weiterbehandler sowie den Wechsel des Patienten in die neue Versorgungseinrichtung. Eine abschließende Evaluation des Projekts ist für Herbst 2020 geplant.</jats:p&gt

Clinical Diagnostics in Human Genetics with Semantic Similarity Searches in Ontologies

The differential diagnostic process attempts to identify candidate diseases that best explain a set of clinical features. This process can be complicated by the fact that the features can have varying degrees of specificity, as well as by the presence of features unrelated to the disease itself. Depending on the experience of the physician and the availability of laboratory tests, clinical abnormalities may be described in greater or lesser detail. We have adapted semantic similarity metrics to measure phenotypic similarity between queries and hereditary diseases annotated with the use of the Human Phenotype Ontology (HPO) and have developed a statistical model to assign p values to the resulting similarity scores, which can be used to rank the candidate diseases. We show that our approach outperforms simpler term-matching approaches that do not take the semantic interrelationships between terms into account. The advantage of our approach was greater for queries containing phenotypic noise or imprecise clinical descriptions. The semantic network defined by the HPO can be used to refine the differential diagnosis by suggesting clinical features that, if present, best differentiate among the candidate diagnoses. Thus, semantic similarity searches in ontologies represent a useful way of harnessing the semantic structure of human phenotypic abnormalities to help with the differential diagnosis. We have implemented our methods in a freely available web application for the field of human Mendelian disorders

Ein strukturierter Versorgungspfad von der Pädiatrie in die Erwachsenenmedizin für Jugendliche und junge Erwachsene mit einer seltenen Erkrankung

Die erfolgreiche Organisation und Umsetzung des Übergangs von Jugendlichen und jungen Erwachsenen mit einer chronischen seltenen Erkrankung aus der Pädiatrie in eine Versorgungsform (Transition) und Versorgungsstruktur (Transfer) der Erwachsenenmedizin ist eine wichtige Aufgabe im dezentral aufgebauten deutschen Gesundheitssystem. Ein mittlerweile in der Praxis erprobtes Programm stellt der strukturierte Versorgungspfad des vom Innovationsfonds des gemeinsamen Bundesausschuss (G‑BA) geförderten Konsortiums TRANSLATE-NAMSE dar (Förderkennzeichen 01NVF16024 TRANSLATE-NAMSE). Grundlage des Übergangs in diesem Programm ist der qualitätsgesicherte Informations- und Kompetenztransfer vom pädiatrischen Behandlungsteam zum adoleszenten Patienten, sowie zur neuen Versorgungseinrichtung. Basierend auf einer strukturierten Epikrise und Erhebung des individuellen Beratungsbedarfs erfolgt, ab dem Alter von 16 Jahren, die strukturierte Transitionsschulung des Patienten durch den Pädiater. Nach erfolgreich absolvierten Transfersprechstunden, gemeinsam mit Vertretern der bisherigen pädiatrischen und der zukünftigen erwachsenenmedizinischen Versorgungseinrichtungen, mündet der Prozess in die Übergabe aller notwendigen medizinischen Unterlagen an den Patienten und den Weiterbehandler sowie den Wechsel des Patienten in die neue Versorgungseinrichtung. Eine abschließende Evaluation des Projekts ist für Herbst 2020 geplant.The successful organization and management of the transition and transfer of adolescents and young adults with a chronic rare disease from pediatric to adult care is an important but complex task in the decentralized German healthcare system. The structured transition pathway of the consortium TRANSLATE-NAMSE, funded by the innovation fund of the Federal Joint Committee (G-BA, funding number 01NVF16024 TRANSLATE-NAMSE) is a program that has meanwhile been tested in practice. The main principle of the transition in this program is the quality-assured transfer of information from the pediatric treatment team to the adolescent patient as well as to the healthcare provider(s) of the adult care facility. Based on a structured assessment and documentation of the individual need for information, the transition training is carried out by the pediatric treatment team for adolescent patients aged 16 years and older. In addition, transfer clinics, with the representatives of the previous pediatric and the future adult healthcare providers and the transfer of all necessary medical documentation to the patient and to the new health care provider are part of the program. A final evaluation of the project is expected in late 2020