Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2145
Steffen Syrbe
Developmental and epileptic encephalopathies comprise a heterogeneous group of monogenic neurodevelopmental disorders characterized by early-onset seizures, marked epileptic activity and abnormal neurocognitive development. The identification of an increasing number of underlying genetic alterations and their pathophysiological roles in cellular signaling drives the way toward novel precision therapies. The implementation of novel treatments that target the underlying mechanisms gives hope for disease modification that will improve not only the seizure burden but also the neurodevelopmental outcome of affected children. So far, beneficial effects are mostly reported in individual trials and small numbers of patients. There is a need for international collaborative studies to define the natural history and relevant outcome measures and to test novel pharmacological approaches.
{"title":"Developmental and epileptic encephalopathies - therapeutic consequences of genetic testing.","authors":"Steffen Syrbe","doi":"10.1515/medgen-2022-2145","DOIUrl":"10.1515/medgen-2022-2145","url":null,"abstract":"<p><p>Developmental and epileptic encephalopathies comprise a heterogeneous group of monogenic neurodevelopmental disorders characterized by early-onset seizures, marked epileptic activity and abnormal neurocognitive development. The identification of an increasing number of underlying genetic alterations and their pathophysiological roles in cellular signaling drives the way toward novel precision therapies. The implementation of novel treatments that target the underlying mechanisms gives hope for disease modification that will improve not only the seizure burden but also the neurodevelopmental outcome of affected children. So far, beneficial effects are mostly reported in individual trials and small numbers of patients. There is a need for international collaborative studies to define the natural history and relevant outcome measures and to test novel pharmacological approaches.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"215-224"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43302021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2151
{"title":"Wissenschaftspreis 2022 der GSK Stiftung für Dr. med. Sarah Kim-Hellmuth (München).","authors":"","doi":"10.1515/medgen-2022-2151","DOIUrl":"10.1515/medgen-2022-2151","url":null,"abstract":"","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"1 1","pages":"257"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42120055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2143
Ilona Krey, Konrad Platzer, Johannes R Lemke
{"title":"Monogenetic epilepsies and how to approach them in 2022.","authors":"Ilona Krey, Konrad Platzer, Johannes R Lemke","doi":"10.1515/medgen-2022-2143","DOIUrl":"10.1515/medgen-2022-2143","url":null,"abstract":"","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"201-205"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44498957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2146
Henrike O Heyne
An epilepsy diagnosis has large consequences for an individual but is often difficult to make in clinical practice. Novel biomarkers are thus greatly needed. Here, we give an overview of how thousands of common genetic factors that increase the risk for epilepsy can be summarized as epilepsy polygenic risk scores (PRS). We discuss the current state of research on how epilepsy PRS can serve as a biomarker for the risk for epilepsy. The high heritability of common forms of epilepsy, particularly genetic generalized epilepsy, indicates a promising potential for epilepsy PRS in diagnosis and risk prediction. Small sample sizes and low ancestral diversity of current epilepsy genome-wide association studies show, however, a need for larger and more diverse studies before epilepsy PRS could be properly implemented in the clinic.
{"title":"Polygenic risk scores in epilepsy.","authors":"Henrike O Heyne","doi":"10.1515/medgen-2022-2146","DOIUrl":"10.1515/medgen-2022-2146","url":null,"abstract":"<p><p>An epilepsy diagnosis has large consequences for an individual but is often difficult to make in clinical practice. Novel biomarkers are thus greatly needed. Here, we give an overview of how thousands of common genetic factors that increase the risk for epilepsy can be summarized as epilepsy polygenic risk scores (PRS). We discuss the current state of research on how epilepsy PRS can serve as a biomarker for the risk for epilepsy. The high heritability of common forms of epilepsy, particularly genetic generalized epilepsy, indicates a promising potential for epilepsy PRS in diagnosis and risk prediction. Small sample sizes and low ancestral diversity of current epilepsy genome-wide association studies show, however, a need for larger and more diverse studies before epilepsy PRS could be properly implemented in the clinic.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"225-230"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46745742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2144
Ilona Krey, Kathrine M Johannesen, Oona Kohnen, Johannes R Lemke
Knowledge of underlying genetic causes of developmental and epileptic encephalopathies (DEE) in adults is still limited when compared to the routine diagnostic approach in similarly affected children. A well-documented longitudinal study of adults with DEE is of utmost importance to understand the natural history of the respective entity. This information is of great value especially for genetic counselling of newly diagnosed children with identical genetic diagnoses and may impact treatment and management of affected individuals. In our meta-analysis we provide an overview of the most recurrent genetic findings across an adult DEE cohort (). The gene mostly associated with a pathogenic or likely pathogenic variant in adult DEE is SCN1A, followed by MECP2 and CHD2. Studies employing exome sequencing and calling of both single nucleotide variants and copy number variants are associated with diagnostic yields of almost 50 %. Finally, we highlight three remarkable cases, each representing the oldest individual ever published with their genetic diagnosis, i. e., Angelman syndrome, Miller-Dieker syndrome, and CAMK2A-related disorder, and describe lessons learned from each of these adults.
{"title":"Genetic testing in adults with developmental and epileptic encephalopathy - what do we know?","authors":"Ilona Krey, Kathrine M Johannesen, Oona Kohnen, Johannes R Lemke","doi":"10.1515/medgen-2022-2144","DOIUrl":"10.1515/medgen-2022-2144","url":null,"abstract":"<p><p>Knowledge of underlying genetic causes of developmental and epileptic encephalopathies (DEE) in adults is still limited when compared to the routine diagnostic approach in similarly affected children. A well-documented longitudinal study of adults with DEE is of utmost importance to understand the natural history of the respective entity. This information is of great value especially for genetic counselling of newly diagnosed children with identical genetic diagnoses and may impact treatment and management of affected individuals. In our meta-analysis we provide an overview of the most recurrent genetic findings across an adult DEE cohort (<math><mi>n</mi><mo>=</mo><mn>1</mn><mo>,</mo><mn>020</mn></math>). The gene mostly associated with a pathogenic or likely pathogenic variant in adult DEE is <i>SCN1A</i>, followed by <i>MECP2</i> and <i>CHD2</i>. Studies employing exome sequencing and calling of both single nucleotide variants and copy number variants are associated with diagnostic yields of almost 50 %. Finally, we highlight three remarkable cases, each representing the oldest individual ever published with their genetic diagnosis, i. e., Angelman syndrome, Miller-Dieker syndrome, and <i>CAMK2A</i>-related disorder, and describe lessons learned from each of these adults.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"207-213"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46078916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-22eCollection Date: 2022-10-01DOI: 10.1515/medgen-2022-2148
F Söhner, V Rolfes, W Hofmann, K Zerres, H Fangerau, M Krischel
In this article we describe and analyse the issue of non-directivity in human genetic counselling in Germany between 1970 and 2010 based on printed sources and oral history interviews. The focus is on the extent to which the ethical aspects in genetic counselling were debated among human geneticists and to what extent aspects of non-directivity were discussed.As the results show, it was not only in retrospect that experts attributed great importance to the autonomy of those seeking advice and rejected "directive" advice, at least in public positions. They considered ethical justification to be central here.
{"title":"[Non-directivity as a guiding category in human genetic counselling in a historical perspective].","authors":"F Söhner, V Rolfes, W Hofmann, K Zerres, H Fangerau, M Krischel","doi":"10.1515/medgen-2022-2148","DOIUrl":"10.1515/medgen-2022-2148","url":null,"abstract":"<p><p>In this article we describe and analyse the issue of non-directivity in human genetic counselling in Germany between 1970 and 2010 based on printed sources and oral history interviews. The focus is on the extent to which the ethical aspects in genetic counselling were debated among human geneticists and to what extent aspects of non-directivity were discussed.As the results show, it was not only in retrospect that experts attributed great importance to the autonomy of those seeking advice and rejected \"directive\" advice, at least in public positions. They considered ethical justification to be central here.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"233-239"},"PeriodicalIF":1.1,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43753091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson's disease and discuss the therapeutic implications.
{"title":"Clinical relevance and translational impact of reduced penetrance in genetic movement disorders.","authors":"Sebastian Heinzel, Deborah Mascalzoni, Tobias Bäumer, Daniela Berg, Meike Kasten, Norbert Brüggemann","doi":"10.1515/medgen-2022-2128","DOIUrl":"10.1515/medgen-2022-2128","url":null,"abstract":"<p><p>Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson's disease and discuss the therapeutic implications.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"151-156"},"PeriodicalIF":1.1,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43496751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-12eCollection Date: 2022-06-01DOI: 10.1515/medgen-2022-2133
Philip Seibler, Aleksandar Rakovic
Movement disorders comprise a clinically, pathologically, and genetically heterogeneous group of diseases associated with the phenomenon of reduced penetrance. Penetrance refers to the likelihood that a clinical condition will occur when a particular genotype is present. Elucidating the cause of reduced penetrance may contribute to more personalized medicine by identifying genetic factors that may prevent individuals from developing disease. Therefore, patient material becomes an irreplaceable resource in this approach. It is needed to identify genetic modifiers of the disease in the first place and to subsequently elucidate underlying mechanisms in endogenous human cell models that provide the entire genetic background.
{"title":"Patient-derived cells - an irreplaceable tool for research of reduced penetrance in movement disorders.","authors":"Philip Seibler, Aleksandar Rakovic","doi":"10.1515/medgen-2022-2133","DOIUrl":"10.1515/medgen-2022-2133","url":null,"abstract":"<p><p>Movement disorders comprise a clinically, pathologically, and genetically heterogeneous group of diseases associated with the phenomenon of reduced penetrance. Penetrance refers to the likelihood that a clinical condition will occur when a particular genotype is present. Elucidating the cause of reduced penetrance may contribute to more personalized medicine by identifying genetic factors that may prevent individuals from developing disease. Therefore, patient material becomes an irreplaceable resource in this approach. It is needed to identify genetic modifiers of the disease in the first place and to subsequently elucidate underlying mechanisms in endogenous human cell models that provide the entire genetic background.</p>","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"125-130"},"PeriodicalIF":1.1,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42973586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-12eCollection Date: 2022-06-01DOI: 10.1515/medgen-2022-2130
Ilona Krey, Robert Meyer, Johanna Tecklenburg, Für Die Junge Humangenetik
{"title":"Das „klinische Jahr“ in der Humangenetik – Zeit für eine Neuauflage?: Perspektiven aus der Jungen Humangenetik.","authors":"Ilona Krey, Robert Meyer, Johanna Tecklenburg, Für Die Junge Humangenetik","doi":"10.1515/medgen-2022-2130","DOIUrl":"10.1515/medgen-2022-2130","url":null,"abstract":"","PeriodicalId":48632,"journal":{"name":"Medizinische Genetik","volume":"34 1","pages":"163-165"},"PeriodicalIF":1.1,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41534672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}