搜索结果：Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V

Die Exomsequenzierung hat in der genetischen Routinediagnostik zunehmend an Bedeutung gewonnen, da die Mehrzahl krankheitsursächlicher Varianten für monogene Erkrankungen in den proteinkodierenden Regionen liegen. Sowohl Punktmutationen (Single Nucleotide Variants, SNV) als auch Kopienzahlvariation (Copy Number Variants, CNV) können damit schnell und kostengünstig detektiert werden und ermöglichen eine Diagnosestellung bei Patient:innen mit einer vermuteten genetischen Erkrankung. Jedoch muss bei diesem Ansatz nicht nur die Pathogenität der gefundenen Variante bewiesen, sondern auch das Gen hinsichtlich der Genotyp-Phänotyp-Assoziation (GPA).evaluiert werden. Die Evidenz für GPA und die Pathogenität verschiedener Varianten variiert hierbei stark zwischen den derzeit bekannten, krankheitsverursachenden Genen. Die genetische Diagnostik seltener Erkrankungen wird durch geringe Fallzahlen, Studien und damit wenig evidenten Informationen erschwert z.B. zu Genfunktionen, Pathogenität von Varianten und phänotypischen Merkmalen. Das Berichten von Varianten in diesen Genen birgt immer das Risiko eines falsch-positiven Befundberichts für die Patient:innen. Das Zurückhalten dieser Erkenntnisse führt jedoch auch dazu, dass die Datenlage für seltene genetische Erkrankungen weiterhin limitiert bleibt. Nicht immer werden Varianten aus Fallberichten und Literatur in kuratierte Datenbanken aufgenommen bzw. übermittelt. Dies liegt auch daran, dass eine aktive Einreichung notwendig ist, wohingegen andere Datenbanken automatisch Varianten aufnehmen. Dies führt dazu, dass zwischen verschiedenen Datenbanken inkonsistente Informationen zu finden sind, sodass der Vergleich verschiedener Datenbanken bei der Bewertung von Varianten und GPA notwendig ist. Durch den rasanten Fortschritt in genetischer Diagnostik und Forschung ergeben sich innerhalb kurzer Zeit viele neue Erkenntnisse zu Genfunktionen, GPA und Pathogenität verschiedener Varianten, sodass eine Re-Evaluation mit zeitlichem Abstand sinnvoll ist, um vormals ungelöste Fälle neu zu bewerten. Die Grundlage dieser publikationsbasierten Dissertation bildet die Studie „Routine Diagnostics Confirm Novel Neurodevelopmental Disorders“ (Jauss*, Schließke* et al. 2022, *geteilte Erstautorenschaft). Die im Rahmen dieser Arbeit durchgeführte Re-Evaluation umfasst die diagnostischen Next-Generation-Sequencing (NGS)-Analysen am Institut für Humangenetik des Universitätsklinikums Leipzig aus den Jahren 2016 bis 2021. Somit ergab sich ein Datensatz, welcher 9449 Analysen umfasste. Eine retrospektive Auswertung wurde für alle Gene durchgeführt, die nur eine begrenzte Evidenz für eine Genotyp-Phänotyp-Assoziation besitzen. Da ein Schwerpunkt des Instituts auf neurologischen Entwicklungsstörungen liegt, stand die Mehrzahl dieser Fälle im Zusammenhang mit Entwicklungsstörungen und/oder Epilepsie. In dieser Re-Evaluation wurden durch systematisches Filtern Fälle identifiziert, bei denen die Pathogenität der Varianten in öffentlichen Datenbanken unzureichend belegt ist. Diagnosen konnten dennoch aufgrund gut charakterisierter Gene, hochspezifischer Phänotypen, etablierter funktioneller Studien oder umfassender phänotypischer Charakterisierung gestellt werden. In weiteren Fällen konnten durch die Re-Evaluation bestehende Genotyp-Phänotyp-Assoziationen um wertvolle genetische und/oder phänotypische Informationen ergänzt werden. Weiterhin konnte für einige Fälle gezeigt werden, dass die diagnostizierte GPA nicht die korrekte Diagnose darstellte. 32 Die Empfehlung, seltene und tendenziell unklare Varianten zu berichten, impliziert auch die Notwendigkeit der Korrektur falsch-positiver Befunde. Hierbei ist die Re-Evaluation von unsicheren Befunden, und ggf. Korrektur von Diagnosen, in regelmäßigen Abständen unerlässlich- sowohl für die Patient:innen als auch für die wissenschaftliche Gemeinschaft. Mit dieser Studie konnte gezeigt werden, dass bereits in der genetischen Routinediagnostik mit wenig Aufwand wertvolle Erkenntnisse für die Erforschung von seltenen Erkrankungen gewonnen werden können. Forschende sollen hierbei ermutigt werden, identifizierte Varianten regelmäßig in öffentlichen Datenbanken zu teilen und durch kurze Fallberichte weitere Evidenz für Genotyp-Phänotyp-Assoziationen zu schaffen.:1.Einführung 1.1 Seltene Erkrankungen und Neurologische Entwicklungsstörungen 1.2 Diagnostik neurologischer Entwicklungsstörungen 1.2.1 Genetische Diagnostik bei NDD 1.2.2 Genetische Forschung bei NDD 1.3 Trio-Exomanalyse 1.3.1 Kandidatengene 1.4 Ableitung der Forschungsfrage 2.Publikation 3.Zusammenfassung 4.Literaturverzeichnis 5.Darstellung des eigenen Beitrags 6.Erklärung über die eigenständige Abfassung der Arbeit 7.Lebenslauf 8.Mitarbeit an Veröffentlichungen 9.Danksagung

Heart transplantation (HT) remains the only therapeutic option that significantly improves long-term survival for patients with end-stage cardiomyopathy. However, clinical practice faces challenges including the shortage of donor organs, increased surgical risks, and limitations in long-term survival. Recent advancements in minimally invasive surgery, precision immunosuppression, xenotransplantation, and artificial heart technologies have substantially improved transplant safety and outcomes; however, a systematic integration of these innovations is lacking. This study reviews technological advancements and current trends in HT to optimize clinical decision-making and promote individualized treatment strategies. A systematic review of literature published between 2015 and 2025 was conducted using PubMed and Web of Science databases. The search focused on five key areas of HT: minimally invasive surgery, donor expansion, precision immunosuppression, xenotransplantation, and postoperative management. Literature screening and analysis were performed independently by two researchers to ensure the objectivity and accuracy of the findings. Minimally invasive techniques, including partial Maryland and robot-assisted surgery, have significantly reduced postoperative bleeding and complications in high-risk patients. Normothermic machine perfusion (NMP) has extended donor heart preservation up to 12 hours, improving marginal donor utilization. Genotype-guided immunosuppressive therapy and donor-derived cell-free DNA (dd-cfDNA) monitoring enhance the precision of immunosuppression management. CRISPR-Cas9-mediated xenotransplantation has enabled successful transplantation of genetically modified pig hearts into humans, with reported survival exceeding 60 days. Magnetic Resonance Imaging (MRI) T1/T2 mapping and implantable hemodynamic monitoring technologies also show promise for the non-invasive early detection of rejection. Technological innovations have greatly enhanced clinical outcomes in HT. However, further long-term data and standardized evidence are necessary. Future efforts should focus on standardizing techniques, translating immune tolerance strategies into clinical practice, and establishing safety frameworks for xenotransplantation.

Background: Posterior segment eye diseases, including age-related macular degeneration and diabetic retinopathy, are preeminent causes of vision loss worldwide. Effective drug delivery to the retina poses an ongoing therapeutic difficulty due to the presence of the anatomical and physiological barriers. Nanotechnology-based drug delivery systems represent a promising strategy to overcome those limitations. Methods: A narrative literature review was conducted using the PubMed, Scopus, and Google Scholar databases, covering publications published between 2020 and 2026. Publications evaluating nanoparticles for the treatment of the vitreoretinal disorders, including pre-clinical in vitro and in vivo studies, were analyzed. Results: Nanocarriers, including liposomes, polymeric nanoparticles, and lipid-based systems, established improved drug bioavailability, stability, and targeted delivery. The analyzed systems facilitate sustained drug release and potentially reduce the prevalence of invasive intravitreal injections. The nanocarriers’ effectiveness is primarily influenced by their physicochemical properties, such as particle size, surface charge, and encapsulation efficiency. Nonetheless, the production costs and safety aspects, including cytotoxicity, oxidative stress, and inflammatory responses, remain as significant limitations. Conclusions: Nanotechnology-based drug delivery systems serve as an auspicious therapeutic approach for posterior segment eye diseases. However, further standardized preclinical and clinical research is required to assure long-term safety, and enable successful clinical transition.

Introduction: The diagnosis of Atypical hemolytic-uremic syndrome (aHUS) is largely imprecise. Improving outcomes requires accurate diagnosis and timely management. Acute kidney damage, thrombocytopenia, and microangiopathic hemolytic anemia are all signs of aHUS. The condition is brought on by pregnancy, and in genetically susceptible women, it progresses to a terrible hemolytic illness marked by widespread endothelium damage and platelet consumption. The sickness is a potentially fatal ailment that demands quick identification and treatment.Case Presentation: Our facility provided treatment for severe anemia, thrombocytopenia, and acute renal damage in a 24-year-old G1P1A0 postpartum lady with Caesarean sectio and a HELLP syndrome suspicion. An aHUS diagnosis was later verified. The condition of the patient failed to improve in the first 24 hours after birth. Inside this presence of TMA, the patient began on daily TPE and ran in parallel prednisone medication (1 mg/kg/day). After six TPE cycles, the laboratory values began to rise.Conclusion: AHUS can be challenging to diagnose early since it frequently mimics other illnesses. To enhance results, proper diagnosis and prompt management are essential. The management strategy includes a multidisciplinary team, early plasmapheresis, and complement inhibition. To lessen the effects of aHUS, TPE should be carried out as soon as feasible on a daily basis.

Background: Ichthyosis is a range of rare, genetically heterogeneous conditions that are skin disorders caused by over-scaling and hindrance in skin barrier. Clinical care has made a significant improvement however; patients experience very serious psychosocial, emotional and societal difficulties. Objective: The objective of this review is to highlight the perception and the quality of life of the patients affected by ichthyosis experience and the role of advocacy and sponsorship organizations in championing patient-centered care. Method: A comprehensive literature search was conducted across databases including PubMed, Scopus, and Google Scholar for articles published up to May 2024. Studies focusing on patient experiences, advocacy efforts, and care strategies in ichthyosis were included. Quality assessment was performed using the Critical Appraisal Skills Program (CASP) for qualitative studies and the Newcastle-Ottawa Scale (NOS) for observational studies. Results: Thematic analysis revealed three findings: (1) high psychological and social load patients face because of visible symptoms, (2) emotional distress and social isolation, and (3) stratification points in communication between patients and healthcare providers. Advocacy organizations like the Foundation for Ichthyosis & Related Skin Types (FIRST) were identified as instrumental in education, psychosocial support, as well as policy advocacy. Conclusion: Ichthyosis management should not only be limited to clinical outcomes but should also focus on emotional and social wellbeing of the patient. The networks of sponsorship and advocacy play a crucial role in closing the care gaps and enabling patients.

Significant progress in comprehensive molecular diagnostics and targeted therapies for advanced malignancies has, in part, led to substantial improvements in patient outcomes. Nevertheless, comprehensive genomic profiling necessitates interdisciplinary discussion of potential clinical recommendations within interdisciplinary molecular tumor boards. (Likely) pathogenic germline variants (PGVs) typically warrant genetic counseling for patients and, where appropriate, their relatives. Concurrently, the rapidly expanding availability of targeted therapies introduces new therapeutic implications based on germline alterations that must be integrated into clinical decision-making. Moreover, the identification of PGVs may not only inform therapy in patients with manifest malignancy but also offer opportunities for targeted chemoprevention.

Induced pluripotent stem cell (iPSC) models of neurodevelopmental disorders (NDDs) have promoted an understanding of commonalities and differences within or across patient populations by revealing the underlying molecular and cellular mechanisms contributing to disease pathology. Here, we focus on developing a human model for PPP2R5D-related NDD, called Jordan syndrome, which has been linked to Early-Onset Parkinson's Disease (EOPD). Here we sought to understand the underlying molecular and cellular phenotypes across multiple cell states and neuronal subtypes in order to gain insight into Jordan syndrome pathology. Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated pathways and neuronal architecture. We then evaluated a CRISPR-based approach for editing heterozygous dominant G-to-A mutations at the transcript level in patient-derived neural stem cells. Our findings show that site-directed RNA editing is influenced by sgRNA length and cell type. These studies support the potential for a CRISPR RNA editor system to selectively edit mutant transcripts harboring G-to-A mutations in neural stem cells while providing an alternative editing technology for those suffering from NDDs.

Next-generation phenotyping (NGP) can be used to compute the similarity of dysmorphic patients to known syndromic diseases. So far, the technology has been evaluated in variant prioritization and classification, providing evidence for pathogenicity if the phenotype matched with other patients with a confirmed molecular diagnosis. In a Nigerian cohort of individuals with facial dysmorphism, we used the NGP tool GestaltMatcher to screen portraits prior to genetic testing and subjected individuals with high similarity scores to exome sequencing (ES). Here, we report on two individuals with global developmental delay, pulmonary artery stenosis, and genital and limb malformations for whom GestaltMatcher yielded Cornelia de Lange syndrome (CdLS) as the top hit. ES revealed a known pathogenic nonsense variant, NM_133433.4: c.598C>T; p.(Gln200*), as well as a novel frameshift variant c.7948dup; p.(Ile2650Asnfs*11) in NIPBL. Our results suggest that NGP can be used as a screening tool and thresholds could be defined for achieving high diagnostic yields in ES. Training the artificial intelligence (AI) with additional cases of the same ethnicity might further increase the positive predictive value of GestaltMatcher.

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive "omics" analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.

Abstract Interconnecting results of previous OMICs studies is of major importance for identifying novel underlying causes of male infertility. To date, information can be accessed mainly through literature search engines and raw data repositories. However, both have limited capacity in identifying relevant publications based on aggregated research results e.g. genes mentioned in images and supplements. To address this gap, we present the Male Fertility Gene Atlas (MFGA), a web tool that enables standardised representation and search of aggregated result data of scientific publications. An advanced search function is provided for querying research results based on study conditions/phenotypes, meta information and genes returning the exact tables and figures from the publications fitting the search request as well as a list of most frequently investigated genes. As basic prerequisite, a flexible data model that can accommodate and structure a very broad range of meta information, data tables and images was designed and implemented for the system. The first version of the system is published at the URL https://mfga.uni-muenster.de and contains a set of 46 representative publications. Currently, study data for 28 different tissue types, 32 different cell types and 20 conditions is available. Also, ∼5,000 distinct genes have been found to be mentioned in at least ten of the publications. As a result, the MFGA is a valuable addition to available tools for research on the epi-/genetics of male infertility. The MFGA enables a more targeted search and interpretation of OMICs data on male infertility and germ cells in the context of relevant publications. Moreover, its capacity for aggregation allows for meta-analyses and data mining with the potential to reveal novel insights into male infertility based on available data.