Medizinische Genetik最新文献

Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the central nervous system. Missed by most standard technologies used in routine diagnosis, pathogenic noncoding repeat expansions have to be searched for using specific techniques such as repeat-primed PCR or specific bioinformatics tools applied to genome data, such as ExpansionHunter. In this review, we focus on GC-rich repeat expansions, which represent at least one third of all noncoding repeat expansions described so far. GC-rich expansions are mainly located in regulatory regions (promoter, 5' untranslated region, first intron) of genes and can lead to either a toxic gain-of-function mediated by RNA toxicity and/or repeat-associated non-AUG (RAN) translation, or a loss-of-function of the associated gene, depending on their size and their methylation status. We herein review the clinical and molecular characteristics of disorders associated with these difficult-to-detect expansions.

X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder, caused by a founder retrotransposon insertion in an intron of the TAF1 gene. This insertion contains a polymorphic hexanucleotide repeat (CCCTCT)_n, the length of which inversely correlates with the age at disease onset (AAO) and other clinical parameters, aligning XDP with repeat expansion disorders. Nevertheless, many other pathogenic mechanisms are conceivably at play in XDP, indicating that in contrast to other repeat disorders, the (CCCTCT)_n repeat may not be the actual (or only) disease cause. Here, we summarize and discuss genetic and molecular aspects of XDP, highlighting the role of the hexanucleotide repeat in age-related disease penetrance and expressivity.

Objectives: The aim of this survey was to investigate the career satisfaction of human genetics residents in Germany and to analyse the influence of intrinsic and extrinsic factors.

Methods: We developed an online survey for the evaluation of a broad range of factors concerning the situation of human genetics residents in Germany using validated questionnaires and adding human genetics specific items to them. Human genetics residents working at institutions with an authorization for specialist training were asked to participate in the online survey. To analyse the situation of specialist training in human genetics and the influence of multiple factors on career satisfaction, descriptive statistics, mean descriptive statistics and comparisons of mean values as well as multiple linear regression analyses were carried out.

Results: Of the 71 institutions contacted, 41 (58 %) provided feedback and reported the number of 114 residents in human genetics. In total, 58 residents completed the questionnaire (50.9 %). Overall career satisfaction was high with a mean score of 30.8 (scale ranging from 8-40). Factors significantly influencing career satisfaction were general life satisfaction, occupational self-efficacy expectations and content with the doctors entitled to the specialty training. Except for the reduced perception to achieve their professional goals expressed by women with children, career satisfaction was influenced by neither gender nor parental status, other sociodemographic factors, variables concerning the personal professional life and the residency in general, the subjective perceived workload nor the site of specialist training. Participation in research activities differed significantly between male and female residents. The residents' assessment of their own professional prospects and the prospects of the subject were consistently positive, even though residents consider the current requirement planning by the GB-A for human geneticists as inappropriate and believe that human genetics is not yet firmly anchored as a specialist discipline in the consciousness of other medical colleagues and the general public.

Conclusions: Career satisfaction of German human genetics residents is generally high and mainly influenced by life satisfaction, occupational self-efficacy expectations and quality of the specialist training. In contrast to other specialties career satisfaction seems to be independent from gender or parental status even though male residents were significantly more often involved in research activities. In order to keep human genetics residents in the specialty, measures that enable balanced professional and care work as well as continuous improvement of specialist education, e. g. through the implementation of structured curricula and continuing education of the doctors entitled to specialist training, is of great importance.

Neurogenetic diseases represent a broad group of diseases with variable genetic causes and clinical manifestations. Among these, polymerase-gamma (POLG)-spectrum disorders are relatively frequent with an estimated disease frequency of ∼1:10.000. Also, mutations in the POLG gene are by far the most important cause for mitochondriopathy. POLG-spectrum disorders usually result in progressive loss of brain function and may involve severe and deadly encephalopathy, seizures, and neuromuscular disease, as well as cardiac and hepatic failure in some cases. Onset of disease may range from birth to late adulthood, and disease duration ranges from weeks in severe cases to decades. There is no curative treatment; current animal models do not faithfully recapitulate human disease, complicating preclinical therapeutic studies. Human-based preclinical model systems must be developed to understand the human disease mechanisms and develop therapeutic approaches. In this review, we provide an overview of the current approaches to model neurogenetic disorders in a human cellular and neuronal environment with a focus on POLG-spectrum disorders. We discuss the necessity of using neuronal cells and the advantages and pitfalls of currently available cell model approaches, namely (i) CRISPR-based (i. e., genetically engineered) and induced pluripotent stem cell (iPSC) (i. e., stem cell like)-derived neuronal models and (ii) the reprogramming of patient-derived cells into iPSCs and derived neurons. Despite the fact that cell models are by definition in vitro systems incapable of recapitulating all aspects of human disease, they are still the reasonable point of start to discover disease mechanisms and develop therapeutic approaches to treat neurogenetic diseases.

The generation of three-dimensional (3D) cancer models is a novel and fascinating development in the study of personalized medicine and tumor-specific drug delivery. In addition to the classical two-dimensional (2D) adherent cell culture models, 3D spheroid and organoid cancer models that mimic the microenvironment of cancer tissue are emerging as an important preclinical model system. 3D cancer models form, similar to cancer, multiple cell-cell and cell-extracellular matrix interactions and activate different cellular cascades/pathways, like proliferation, quiescence, senescence, and necrotic or apoptotic cell death. Further, it is possible to analyze genetic variations and mutations, the microenvironment of cell-cell interactions, and the uptake of therapeutics and nanoparticles in nanomedicine. Important is also the analysis of cancer stem cells (CSCs), which could play key roles in resistance to therapy and cancer recurrence. Tumor spheroids can be generated from one tumor-derived cell line or from co-culture of two or more cell lines. Tumor organoids can be derived from tumors or may be generated from CSCs that differentiate into multiple facets of cancerous tissue. Similarly, tumorspheres can be generated from a single CSC. By transplanting spheroids and organoids into immune-deficient mice, patient-derived xenografts can serve as a preclinical model to test therapeutics in vivo. Although the handling and analysis of 3D tumor spheroids and organoids is more complex, it will provide insights into various cancer processes that cannot be provided by 2D culture. Here a short overview of 3D tumor systems as preclinical models is provided.

The human retina is a highly structured and complex neurosensory tissue central to perceiving and processing visual signals. In a healthy individual, the close interplay between the neuronal retina, the adjacent retinal pigment epithelium and the underlying blood supply, the choriocapillaris, is critical for maintaining eyesight over a lifetime. An impairment of this delicate and metabolically highly active system, caused by genetic alteration, environmental impact or both, results in a multitude of pathological phenotypes of the retina. Understanding and treating these disease processes are motivated by a marked medical need in young as well as in older patients. While naturally occurring or gene-manipulated animal models have been used successfully in ophthalmological research for many years, recent advances in induced pluripotent stem cell technology have opened up new avenues to generate patient-derived retinal model systems. Here, we explore to what extent these cellular models can be useful to mirror human pathologies in vitro ultimately allowing to analyze disease mechanisms and testing treatment options in the cell type of interest on an individual patient-specific genetic background.

Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous cardiac disease that is mainly characterized by left ventricular hypertrophy in the absence of any additional cardiac or systemic disease. HCM is genetically heterogeneous, inherited mainly in an autosomal dominant pattern, and so far pathogenic variants have been identified in more than 20 genes, mostly encoding proteins of the cardiac sarcomere. Based on its variable penetrance and expressivity, pathogenicity of newly identified variants often remains unsolved, underlining the importance of cellular and tissue-based models that help to uncover causative genetic alterations and, additionally, provide appropriate systems for the analysis of disease hallmarks as well as for the design and application of new therapeutic strategies like drug screenings and genome/base editing approaches. Here, we review the current state of cellular and tissue-engineered models and provide future perspectives for personalized therapeutic strategies of HCM.