745 results on '"Klaus Zerres"'
Search Results
2. Serotonergic Contributions to Human Brain Aggression Networks
- Author
-
Martin Klasen, Dhana Wolf, Patrick D. Eisner, Thomas Eggermann, Klaus Zerres, Florian D. Zepf, René Weber, and Klaus Mathiak
- Subjects
serotonin ,aggression ,amygdala ,tryptophan depletion ,PFC ,supramarginal gyrus ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene (MAOA) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and MAOA genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and MAOA genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and MAOA genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers.
- Published
- 2019
- Full Text
- View/download PDF
3. Characteristics of Intracranial Aneurysms in the Else Kröner-Fresenius Registry of Autosomal Dominant Polycystic Kidney Disease
- Author
-
Hartmut P.H. Neumann, Angelica Malinoc, Janina Bacher, Zinaida Nabulsi, Vera Ivanovas, Nadine Ortiz Bruechle, Irina Mader, Michael M. Hoffmann, Peter Riegler, Annette Kraemer-Guth, Christian Burchardi, Elke Schaeffner, Rodolfo S. Martin, Pablo J. Azurmendi, Klaus Zerres, Cordula Jilg, Charis Eng, and Sven Gläsker
- Subjects
Intracranial aneurysms ,Autosomal dominant polycystic kidney disease ,Preventive medicine ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Patients who harbor intracranial aneurysms (IAs) run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD). Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. Methods: We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Results: Of 463 eligible ADPKD patients from the population base of Germany, 32 (7%) were found to have IAs, diagnosed at the age of 2–71 years, 19 females and 13 males. Twenty (63%) of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%), IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93%) had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14%) had MR angiography. Conclusion: In ADPKD, rupture of IAs occurs frequently before the start of dialysis, is only infrequently associated with a family history of IAs or subarachnoid hemorrhage, and is associated with mutations either of the PKD1 or the PKD2 gene of any type. Screening for IAs is widely insufficiently performed, should not be restricted to families with a history of cerebral events and should be started before end-stage renal failure.
- Published
- 2012
- Full Text
- View/download PDF
4. Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing.
- Author
-
Martin M J Kirschner, Mirle Schemionek, Claudia Schubert, Nicolas Chatain, Stephanie Sontag, Susanne Isfort, Nadina Ortiz-Brüchle, Karla Schmitt, Luisa Krüger, Klaus Zerres, Martin Zenke, Tim H Brümmendorf, and Steffen Koschmieder
- Subjects
Medicine ,Science - Abstract
In order to assess the feasibility of amplicon-based parallel next generation sequencing (NGS) for the diagnosis of myeloproliferative neoplasms (MPN), we investigated multiplex-PCR of 212 amplicons covering genomic mutational hotspots in 48 cancer-related genes. Samples from 64 patients with MPN and five controls as well as seven (myeloid) cell lines were analyzed. Healthy donor and reactive erythrocytosis samples showed several frequent single-nucleotide polymorphisms (SNPs) but no known pathogenic mutation. Sequencing of the cell lines confirmed the presence of the known mutations. In the patient samples, JAK2 V617F was present in all PV, 4 of 10 ET, and 16 of 19 MF patients. The JAK2 V617F allele burden was different in the three groups (ET, 33+/-22%; PV 48+/-28% and MF 68+/- 29%). Further analysis detected both previously described and undescribed mutations (i.e., G12V NRAS, IDH1 R132H, E255G ABL, and V125G IDH1 mutations). One patient with lymphoid BC/Ph+ ALL who harbored a T315I ABL mutation and was treated with ponatinib was found to have developed a newly acquired V216M TP53 mutation (12% of transcripts) when becoming resistant to ponatinib. Ponatinib led to a decrease of ABL T315I positive transcripts from 47% before ponatinib treatment to 16% at the time of ponatinib resistance in this patient, suggesting that both TP53 and ABL mutations were present in the same clone and that the newly acquired TP53 mutation might have caused ponatinib resistance in this patient. In conclusion, amplicon-sequencing-based NGS allows simultaneous analysis of multiple MPN associated genes for diagnosis and during treatment and measurement of the mutant allele burden.
- Published
- 2015
- Full Text
- View/download PDF
5. Holger Höhn zum 80. Geburtstag und der mühsame Beginn der Humangenetik in Würzburg vor mehr als 40 Jahren
- Author
-
Tiemo Grimm and Klaus Zerres
- Subjects
Genetics ,Genetics (clinical) - Published
- 2023
6. Preconception carrier screening as an alternative reproductive option prior to newborn screening for severe recessive disorders
- Author
-
Sabine Rudnik-Schöneborn and Klaus Zerres
- Subjects
Genetics ,Genetics (clinical) - Published
- 2022
7. Data from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Author
-
Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann
- Abstract
Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs ∼US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age ≤40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]
- Published
- 2023
8. Supplementary Table 1 Legends and References from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Author
-
Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann
- Abstract
Supplementary Table 1 Legends and References from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Published
- 2023
9. Supplementary Table 1 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Author
-
Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann
- Abstract
Supplementary Table 1 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Published
- 2023
10. Other Supporting Colleagues from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Author
-
Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann
- Abstract
Other Supporting Colleagues from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Published
- 2023
11. Supplementary Table 2 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Author
-
Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann
- Abstract
Supplementary Table 2 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
- Published
- 2023
12. MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behavior in males.
- Author
-
Thorben Schlüter, Oliver Winz, Karsten Henkel, Thomas Eggermann, Siamak Mohammadkhani-Shali, Claudia Dietrich, Alexander Heinzel, Michel G. Decker, Paul Cumming, Klaus Zerres, Markus Piel, Felix M. Mottaghy, and Ingo Vernaleken
- Published
- 2016
- Full Text
- View/download PDF
13. The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: A TBSS-based diffusion tensor imaging study.
- Author
-
Thomas Nickl-Jockschat, Tony Stöcker, Valentin Markov, Axel Krug, Ruihuang Huang, Frank Schneider, Ute Habel, Klaus Zerres, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, N. Jon Shah, and Tilo Kircher
- Published
- 2012
- Full Text
- View/download PDF
14. Effect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals.
- Author
-
Axel Krug, Vanessa Nieratschker, Valentin Markov, Sören Krach, Andreas Jansen, Klaus Zerres, Thomas Eggermann, Tony Stöcker, N. Jon Shah, Jens Treutlein, Thomas W. Mühleisen, and Tilo Kircher
- Published
- 2010
- Full Text
- View/download PDF
15. COMT genotype and its role on hippocampal-prefrontal regions in declarative memory.
- Author
-
Sören Krach, Andreas Jansen, Axel Krug, Valentin Markov, Markus Thimm, Abigail J. Sheldrick, Thomas Eggermann, Klaus Zerres, Tony Stöcker, N. Jon Shah, and Tilo Kircher
- Published
- 2010
- Full Text
- View/download PDF
16. The effect of G72 genotype on neural correlates of memory encoding and retrieval.
- Author
-
Andreas Jansen, Sören Krach, Axel Krug, Valentin Markov, Markus Thimm, Frieder M. Paulus, Klaus Zerres, Tony Stöcker, N. Jon Shah, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, and Tilo Kircher
- Published
- 2010
- Full Text
- View/download PDF
17. The effect of Neuregulin 1 on neural correlates of episodic memory encoding and retrieval.
- Author
-
Axel Krug, Valentin Markov, Sören Krach, Andreas Jansen, Klaus Zerres, Thomas Eggermann, Tony Stöcker, N. Jon Shah, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, and Tilo Kircher
- Published
- 2010
- Full Text
- View/download PDF
18. Genetic variation in schizophrenia-risk-gene dysbindin 1 modulates brain activation in anterior cingulate cortex and right temporal gyrus during language production in healthy individuals.
- Author
-
Valentin Markov, Axel Krug, Soeren Krach, Carin Whitney, Thomas Eggermann, Klaus Zerres, Tony Stöcker, N. Joni Shah, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, and Tilo Kircher
- Published
- 2009
- Full Text
- View/download PDF
19. A putative high risk diplotype of the G72 gene is in healthy individuals associated with better performance in working memory functions and altered brain activity in the medial temporal lobe.
- Author
-
Andreas Jansen, Sören Krach, Axel Krug, Valentin Markov, Thomas Eggermann, Klaus Zerres, Tony Stöcker, N. Jon Shah, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, and Tilo Kircher
- Published
- 2009
- Full Text
- View/download PDF
20. Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals.
- Author
-
Axel Krug, Valentin Markov, Thomas Eggermann, Sören Krach, Klaus Zerres, Tony Stöcker, N. Jon Shah, Frank Schneider, Markus M. Nöthen, Jens Treutlein, Marcella Rietschel, and Tilo Kircher
- Published
- 2008
- Full Text
- View/download PDF
21. Do non-invasive prenatal tests promote discrimination against people with Down syndrome? What should be done?
- Author
-
Wolfgang Holzgreve, Sabine Rudnik-Schöneborn, and Klaus Zerres
- Subjects
medicine.medical_specialty ,Down syndrome ,Genetic counseling ,Noninvasive Prenatal Testing ,0603 philosophy, ethics and religion ,Preimplantation genetic diagnosis ,03 medical and health sciences ,Pregnancy ,medicine ,Humans ,Psychiatry ,0303 health sciences ,medicine.diagnostic_test ,Reproductive autonomy ,business.industry ,030305 genetics & heredity ,Non invasive ,Obstetrics and Gynecology ,06 humanities and the arts ,Social Discrimination ,medicine.disease ,Pediatrics, Perinatology and Child Health ,Amniocentesis ,Female ,060301 applied ethics ,Down Syndrome ,Trisomy ,business - Abstract
By implementation of non-invasive prenatal testing (NIPT) for the diagnosis of Down syndrome (DS) in maternity care, an ethical debate is newly inflamed how to deal with this information. Fears of the consequences of an increased use of NIPT are justified with the same arguments when amniocentesis and preimplantation genetic diagnosis (PGD) were introduced decades ago. It can be expected that the prevalence of people with DS would significantly increase in Western societies as a result of the increasing age of pregnant women and the improved medical care for people with DS. The net effect as to whether an increasing uptake of NIPT will result in more abortions of fetuses with trisomy 21 cannot be reliably estimated. This holds true since more and more couples will use results of NIPT for information only, but will not opt for termination of pregnancy. Although parents love their children with DS, in a society where reproductive autonomy is seen as an achievement, access to NIPT cannot be limited. On this background, comprehensive and qualified pretest counseling is vital, also to avoid possible stigmatization of people with DS and as the resulting consequence to avoid feared deterioration in their living conditions, for which, however, there is no evidence to date. The personal view of a mother of a child with DS illustrates the complexity in dealing with NIPT, which does not allow simple answers and must be understood as a challenge for society as a whole.
- Published
- 2021
22. Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants
- Author
-
Alper Soylu, Elke Wühl, Max C. Liebau, Guillaume Dorval, Wanja Bernhardt, Rukshana Shroff, Salim Caliskan, Laura Massella, Gordana Miloševski-Lomić, Ludwig Patzer, Juan David Gonzalez Rodriguez, Klaus Zerres, Katarzyna Taranta-Janusz, Francisco de la Cerda Ojeda, Bahriye Atmis, Bodo B. Beck, Jens König, Nadejda Ranguelov, Claudia Kowalewska, Jörg Dötsch, Florian Erger, Augustina Jankauskiene, Alberto Caldas Afonso, Markus Feldkoetter, Svetlana Papizh, Olivia Boyer, Jérôme Harambat, Franziska Grundmann, Matthias Galiano, Jun Oh, Claire Dossier, Jacques Lombet, Dieter Haffner, Gema Ariceta, Raphael Schild, Ismail Dursun, Ibrahim Gökce, Stella Stabouli, Marcus R. Benz, Rina Rus, Martin Bald, Michaela Gessner, Mieczysław Litwin, Neveen A. Soliman, Djalila Mekahli, Francesco Emma, Nurver Akinci, Loai A. Eid, Cengiz Candan, Alev Yilmaz, Anja Buescher, Lale Sever, Barbara Uetz, Julia Thumfart, Donald Wurm, Beata Bienias, Nadina Ortiz-Bruechle, Ali Duzova, Germana Longo, Przemysław Sikora, Oliver Gross, Susanne Schaefer, Yılmaz Tabel, Sabine Ponsel, Karsten Häffner, Franz Schaefer, Antonio Mastrangelo, Ana Teixeira, Bruno Ranchin, Günter Klaus, Maria Szczepańska, Claudia Dafinger, Andreea Rachisan, Monika Miklaszewska, Aurélie De Mul, Hulya Nalcacioglu, Sevgi Mir, Denis Morin, Katarzyna Zachwieja, Bärbel Lange-Sperandio, William Morello, Marc Fila, Jan Halbritter, Houweyda Jilani, Ute Derichs, Aurelia Morawiec-Knysak, Laure Collard, Małgorzata Stańczyk, Felix Lechner, Francesca Mencarelli, Jakub Zieg, Oliver Dunand, Klaus Arbeiter, Kathrin Burgmaier, Carsten Bergmann, Ilona Zagozdzon, Tomáš Seeman, Larisa Prikhodina, Nakysa Hooman, Lutz T. Weber, Björn Buchholz, Leonie Brinker, Nathalie Godefroid, Simone Wygoda, Hagen Staude, and UCL - (SLuc) Service de pédiatrie générale
- Subjects
0301 basic medicine ,fibrocystin ,030232 urology & nephrology ,Fibrocystin ,fibrocystic hepatorenal disease ,Receptors, Cell Surface ,Disease ,Kidney ,Ciliopathies ,03 medical and health sciences ,0302 clinical medicine ,Ultrasound ,Polycystic kidney disease ,medicine ,Missense mutation ,Humans ,Child ,Genetic Association Studies ,Polycystic Kidney, Autosomal Recessive ,Genetics ,polycystic kidney disease ,biology ,PKD ,Cilium ,Protein ,cilia ,Encodes ,medicine.disease ,Phenotype ,Autosomal Recessive Polycystic Kidney Disease ,030104 developmental biology ,Nephrology ,Child, Preschool ,Mutation ,biology.protein ,ciliopathies ,Mutations - Abstract
Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches. German Society for Pediatric Nephrology (GPN); ESCAPE Network; European Society for Paediatric Nephrology (ESPN); German PKD foundation; Koeln Fortune program; GEROK program of the Medical Faculty of University of Cologne; Marga and Walter Boll-Foundation; German Federal Ministry of Research and Education (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1515, 01GM1903]; working group CAKUT of the ESPN; working group Inherited Kidney Diseases of the ESPN We thank the German Society for Pediatric Nephrology (GPN) and the ESCAPE Network for their support. We thank Mr Mathias Burgmaier (Aachen) and Mr Samuel Kilian (Heidelberg) for support in conducting statistical analysis. ML was supported by grants of the GPN, the European Society for Paediatric Nephrology (ESPN), the German PKD foundation, the Koeln Fortune program, the GEROK program of the Medical Faculty of University of Cologne, and the Marga and Walter Boll-Foundation. FS, CB, and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne, as well as the Marga and Walter Boll-Foundation. This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). The work was supported by the working groups CAKUT and Inherited Kidney Diseases of the ESPN.
- Published
- 2021
23. [Genetic counseling in Germany: development of demand]
- Author
-
Jörg, Schmidtke, Jörg T, Epplen, Ralf, Glaubitz, Tiemo, Grimm, R Peter, Nippert, Holger, Tönnies, Klaus, Zerres, and Irmgard, Nippert
- Subjects
National Health Programs ,Germany ,Humans ,Genetic Counseling ,Genetic Testing ,Referral and Consultation - Abstract
With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law.Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database.Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue.
- Published
- 2020
24. [Targeted Early Detection and Prevention of Hereditary Colorectal Carcinomas]
- Author
-
Klaus, Zerres, Larissa, Arning, Beatrix, Böckmann, Anne, Purczeld, and Bianca, Miterski
- Subjects
Adult ,Male ,Young Adult ,Adolescent ,Germany ,Humans ,Female ,Genetic Predisposition to Disease ,Middle Aged ,Colorectal Neoplasms ,Early Detection of Cancer ,Aged - Abstract
Every year, about 60 000 people in Germany contract colo-rectal carcinoma. Hereditary factors are the cause in approx. 5 % and those affected often fall ill at a young age. Often there are concrete indications of an individual high risk in affected families. The identification of persons at risk enables a targeted early detection and prevention of cancer as an important interdisciplinary medical task. The current AWMF guideline "Colorectal carcinoma" makes concrete statements in this regard.
- Published
- 2020
25. Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies
- Author
-
Florian Kraft, Matthias Begemann, Thomas Eggermann, Stephanie Demuth, Klaus Zerres, Martin Häusler, Sabine Busse, Robert Meyer, Herdit M. Schüler, Miriam Elbracht, Ingo Kurth, and Daniela Dey
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Familial transmission ,030105 genetics & heredity ,Audiology ,03 medical and health sciences ,Young Adult ,Neurodevelopmental disorder ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Language Development Disorders ,Autistic Disorder ,Child ,Genetics (clinical) ,Exome sequencing ,Dysmorphic facies ,business.industry ,Facies ,Middle Aged ,medicine.disease ,Developmental disorder ,030104 developmental biology ,Phenotype ,Child, Preschool ,Speech delay ,Autism ,Female ,medicine.symptom ,business ,Transcription Factors - Abstract
De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.
- Published
- 2020
26. Targeted Early Detection and Prevention of Hereditary Colorectal Carcinomas
- Author
-
Klaus Zerres, Beatrix Böckmann, Anne Purczeld, Larissa Arning, and Bianca Miterski
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Medizin ,Early detection ,Cancer ,General Medicine ,Guideline ,medicine.disease ,Lynch syndrome ,03 medical and health sciences ,Young age ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Family medicine ,Carcinoma ,Medicine ,030211 gastroenterology & hepatology ,business - Abstract
Every year, about 60 000 people in Germany contract colo-rectal carcinoma. Hereditary factors are the cause in approx. 5 % and those affected often fall ill at a young age. Often there are concrete indications of an individual high risk in affected families. The identification of persons at risk enables a targeted early detection and prevention of cancer as an important interdisciplinary medical task. The current AWMF guideline "Colorectal carcinoma" makes concrete statements in this regard.
- Published
- 2020
27. Basics of Related Medical Disciplines
- Author
-
Esther Strittmatter, Christian Postert, Gereon Heuft, Klaus Zerres, Hanno J. Bolz, Georg Romer, Eva Seemanova, Tiemo Grimm, and Dagmar Weise
- Subjects
medicine.medical_specialty ,business.industry ,Hearing loss ,Psychosomatic medicine ,Hearing screening ,3. Good health ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Family medicine ,otorhinolaryngologic diseases ,Child and adolescent psychiatry ,Medicine ,medicine.symptom ,business ,Genetic diagnosis - Abstract
By using the example of hearing loss, an overview is given on genetics, new diagnostic developments and their applications. Owing to novel high-throughput technologies of DNA sequencing, most patients now can get a genetic diagnosis for several reasons, in the routine workup after failed newborn hearing screening but also in cases of hearing loss manifesting later in life.
- Published
- 2019
28. Genetic Risk: Computation
- Author
-
Tiemo Grimm, Bertram Müller‐Myhsok, and Klaus Zerres
- Published
- 2017
29. Das Oral-History-Projekt – Lehren aus der Geschichte unseres Faches
- Author
-
Klaus Zerres
- Subjects
Genetics ,Genetics (clinical) - Published
- 2021
30. Nichtinvasive Pränataldiagnostik – eine gesamtgesellschaftliche Herausforderung
- Author
-
Klaus Zerres
- Subjects
03 medical and health sciences ,030219 obstetrics & reproductive medicine ,0302 clinical medicine ,business.industry ,Medicine ,030212 general & internal medicine ,business - Published
- 2017
31. Cortico-limbic connectivity in MAOA -L carriers is vulnerable to acute tryptophan depletion
- Author
-
Florian D. Zepf, Mikhail Zvyagintsev, Klaus Zerres, Dhana Wolf, Klaus Mathiak, Thomas Eggermann, Krystyna A. Mathiak, Patrick Eisner, Pegah Sarkheil, Albrecht Eisert, and Martin Klasen
- Subjects
Serotonergic ,Amygdala ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Prefrontal cortex ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,Resting state fMRI ,biology ,030227 psychiatry ,medicine.anatomical_structure ,nervous system ,Neurology ,biology.protein ,Neurology (clinical) ,Serotonin ,Anatomy ,Monoamine oxidase A ,Functional magnetic resonance imaging ,Psychology ,Insula ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
INTRODUCTION A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. METHODS Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. RESULTS Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. CONCLUSION MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
32. Gesellschaftlicher Diskurs zur Präimplantationsdiagnostik im Spiegel von Debatten und Stellungnahmen
- Author
-
Christine Scholz and Klaus Zerres
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,Genetics ,Reproductive medicine ,medicine ,business ,Genetics (clinical) - Published
- 2016
33. Präimplantationsdiagnostik im Europavergleich
- Author
-
Sandra Geffroy and Klaus Zerres
- Subjects
Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,030219 obstetrics & reproductive medicine ,0302 clinical medicine ,Political science ,Genetics ,medicine ,030212 general & internal medicine ,Genetics (clinical) - Abstract
Zusammenfassung Die rechtlichen Regelungen der Präimplantationsdiagnostik (PID) in Europa sind sehr heterogen. In der Folge unterscheidet sich die Praxis der PID erheblich. Während einzelne Länder wie England auf eine sehr lange Praxis zurückblicken können, sind die rechtlichen Rahmenbedingungen in anderen Ländern wie Deutschland oder der Schweiz erst in den letzten Jahren geschaffen worden, sodass die Erfahrungen aus diesen Ländern sehr begrenzt sind. Das Präimplantationsdiagnostik Consortium der European Society of Human Reproduction and Embryology (ESHRE) hat die Erfahrungen mit der PID von fast 20 Jahren vorbildlich dokumentiert und regelmäßig ausgewertet, sodass umfassende Daten zur Praxis der PID verfügbar sind. Mit dem vorliegenden Beitrag soll für ausgewählte Aspekte ein Überblick über den Stand der PID in Europa gegeben werden, der aufgrund der sehr heterogenen Regelungen keinen Anspruch auf Vollständigkeit erheben kann.
- Published
- 2016
34. Wie sollen wir mit pränatalen Bluttests umgehen?
- Author
-
Silke Koppermann and Klaus Zerres
- Subjects
Gynecology ,medicine.medical_specialty ,Philosophy ,medicine - Abstract
Der nicht-invasive molekulargenetische Test (NIPT) zum Vorliegen von Trisomien wird voraussichtlich ab Herbst 2020 Kassenleistung. Dieser Bluttest stellt eine ungefahrliche Alternative zur risikoreichen Amniozentese dar. Kritiker erheben jedoch ethische Einwande. Wie sollten wir NIPT handhaben?
- Published
- 2019
35. Autopsiebefunde bei einem adulten Fall von spinaler Muskelatrophie
- Author
-
Joachim Weis, Klaus Zerres, Kay Nolte, and Sabine Rudnik-Schöneborn
- Published
- 2019
36. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia
- Author
-
Klaus Zerres, Stanley F. Nelson, Catriona McLean, Michael Yourshaw, Joanna C. Jen, Sabine Rudnik-Schöneborn, Andrew J. Kornberg, Jijun Wan, Erik Andersen, Kate Pope, Monique M. Ryan, Carla M. Koehler, Janos Steffen, Jörg Joseph, Katherine B. Howell, Hafsa Mamsa, and Paul J. Lockhart
- Subjects
Male ,Models, Molecular ,0301 basic medicine ,Pathology ,Embryo, Nonmammalian ,Neurodegenerative ,Mitochondrion ,Medical and Health Sciences ,Mitochondrial Dynamics ,Animals, Genetically Modified ,Cohort Studies ,Neurodevelopmental disorder ,Models ,Mutant protein ,2.1 Biological and endogenous factors ,Phosphate Transport Proteins ,Missense mutation ,Aetiology ,Amino Acids ,Cells, Cultured ,Zebrafish ,Cell Line, Transformed ,Pediatric ,Cultured ,Nonmammalian ,SLC25A46 ,Brain ,Single Nucleotide ,Magnetic Resonance Imaging ,Mitochondria ,Cell biology ,mitochondrial fusion ,Embryo ,Neurological ,optic atrophy spectrum disorder ,Female ,Mitochondrial fission ,medicine.medical_specialty ,Cells ,Pontocerebellar hypoplasia ,Genetically Modified ,Biology ,Polymorphism, Single Nucleotide ,Cell Line ,Mitochondrial Proteins ,03 medical and health sciences ,Rare Diseases ,Atrophy ,Cerebellar Diseases ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Neurology & Neurosurgery ,pontocerebellar hypoplasia ,Psychology and Cognitive Sciences ,Neurosciences ,Molecular ,Infant ,Original Articles ,medicine.disease ,Brain Disorders ,Orphan Drug ,030104 developmental biology ,Transformed ,Mutation ,Congenital Structural Anomalies ,Neurology (clinical) - Abstract
Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.
- Published
- 2016
37. Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype ofBICD2mutations
- Author
-
Thomas Eggermann, Florian Deden, Alfred Yamoah, Anand Goswami, Bernd Sellhaus, Kristl G. Claeys, Katja Eggermann, Dagmar Wieczorek, Joachim Weis, Klaus Zerres, and Sabine Rudnik-Schöneborn
- Subjects
0301 basic medicine ,Weakness ,Physiology ,Upper motor neuron ,Spinal muscular atrophy ,Anatomy ,Gene mutation ,Biology ,medicine.disease ,Lower motor neuron ,Muscle atrophy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Physiology (medical) ,Corticospinal tract ,medicine ,Spinal muscular atrophy with lower extremity predominance ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Introduction Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). Methods We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. Results We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. Conclusion These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496–500, 2016
- Published
- 2016
38. NSD1duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features
- Author
-
Katja Eggermann, Klaus Zerres, Miriam Elbracht, Alexia Bach, Andrea Luczay, Nadina Ortiz Brüchle, Jana Sachwitz, György Fekete, Vaidutis Kučinskas, Thomas Eggermann, Stephanie Spranger, Aušra Matulevičienė, and Robert Meyer
- Subjects
0301 basic medicine ,Genetics ,Chromosome 7 (human) ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Sotos syndrome ,Silver–Russell syndrome ,Karyotype ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,parasitic diseases ,Gene duplication ,Cohort ,medicine ,Copy-number variation ,Genetics (clinical) ,Genetic testing - Abstract
Silver-Russell syndrome (SRS) is a growth retardation syndrome characterized by intrauterine and postnatal growth retardation, relative macrocephaly and protruding forehead, body asymmetry and feeding difficulties. Nearly 50% of cases show a hypomethylation in 11p15.5, in 10% maternal uniparental disomy of chromosome 7 is present. A significant number of patients with SRS features also exhibit chromosomal aberrations. We analyzed 43 individuals referred for SRS genetic testing by molecular karyotyping. Pathogenic variants could be detected in five of them, including a NSD1 duplication in 5q35 and a 14q32 microdeletion. NSD1 deletions are detectable in overgrowth disorders (Sotos syndrome and Beckwith-Wiedemann syndrome), whereas NSD1 duplications are associated with growth retardation. The 14q32 deletion is typically associated with Temple syndrome (TS14), but the identification of a patient in our cohort reflects the clinical overlap between TS14 and SRS. As determination of molecular subtypes is the basis for a directed counseling and therapy, the identification of pathogenic variants in >10% of the total cohort of patients referred for SRS testing and in >16% of characteristic individuals with the characteristic SRS phenotype confirms the need to apply molecular karyotyping in this cohort.
- Published
- 2016
39. Influences of Pregnancy on Different Genetic Subtypes of Non-Dystrophic Myotonia and Periodic Paralysis
- Author
-
Klaus Zerres, Sabine Rudnik-Schöneborn, and Martina Witsch-Baumgartner
- Subjects
Adult ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Myotonia ,Paralyses, Familial Periodic ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Chloride Channels ,Pregnancy ,medicine ,Humans ,NAV1.4 Voltage-Gated Sodium Channel ,CLCN1 ,030219 obstetrics & reproductive medicine ,biology ,Myotonia congenita ,business.industry ,Non dystrophic myotonia ,Obstetrics and Gynecology ,Periodic paralysis ,medicine.disease ,nervous system diseases ,body regions ,Reproductive Medicine ,Anesthesia ,biology.protein ,Female ,business ,030217 neurology & neurosurgery ,Myotonic Disorders - Abstract
Background: There are only few reports of pregnancy and delivery in non-dystrophic myotonia or periodic paralysis caused by CLCN1 or SCN4A gene mutations. Methods: We report the medical histories and personal attitudes of 5 unrelated German patients, 2 following autosomal recessive inheritance (case 1; most likely and case 2; confirmed Becker disease) and 3 following autosomal dominant inheritance (case 3; CLCN1 mutation, cases 4-5; SCN4A mutations), who delivered a total of 9 children. Results: Apart from case 5 with periodic paralysis, who had 5 early miscarriages and pre-eclampsia resulting in cesarean delivery, there was no evidence of increased obstetric complication rates, and neonatal outcome was favorable. In all patients, there was aggravation of myotonia or weakness in pregnancy, followed by a short-term improvement after delivery in cases 2 and 3. Mexiletine medication improved the clinical features significantly in case 2 but was unable to control pregnancy-related deterioration. In case 4 (and her sister) and case 5, there was a clear disease aggravation in pregnancy resulting in hospitalization or repeated neurological examinations. Conclusion: Pregnancy can be regarded as a strong triggering factor in inherited non-dystrophic myotonias and periodic paralysis, regardless of the underlying gene defect.
- Published
- 2016
40. Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease
- Author
-
Kathrin Burgmaier, Kevin Kunzmann, Gema Ariceta, Carsten Bergmann, Anja Katrin Buescher, Mathias Burgmaier, Ismail Dursun, Ali Duzova, Loai Eid, Florian Erger, Markus Feldkoetter, Matthias Galiano, Michaela Geßner, Heike Goebel, Ibrahim Gokce, Dieter Haffner, Nakysa Hooman, Bernd Hoppe, Augustina Jankauskiene, Guenter Klaus, Jens König, Mieczyslaw Litwin, Laura Massella, Djalila Mekahli, Engin Melek, Sevgi Mir, Lars Pape, Larisa Prikhodina, Bruno Ranchin, Raphael Schild, Tomas Seeman, Lale Sever, Rukshana Shroff, Neveen A. Soliman, Stella Stabouli, Malgorzata Stanczyk, Yilmaz Tabel, Katarzyna Taranta-Janusz, Sara Testa, Julia Thumfart, Rezan Topaloglu, Lutz Thorsten Weber, Dorota Wicher, Elke Wühl, Simone Wygoda, Alev Yilmaz, Katarzyna Zachwieja, Ilona Zagozdzon, Klaus Zerres, Jörg Dötsch, Franz Schaefer, Max Christoph Liebau, Nadejda Ranguelov, Nathalie Godefroid, Laure Collard, Jacques Lombet, Julie Maquet, Gesa Schalk, Uwe Querfeld, Bodo B. Beck, Thomas Benzing, Reinhard Buettner, Franziska Grundmann, Christine Kurschat, Kerstin Benz, Anja Tzschoppe, Björn Buchholz, Rainer Buescher, Karsten Häffner, Martin Pohl, Oliver Gross, Jenny Krügel, Johanna Stock, Ludwig Patzer, Jun Oh, Wanja Bernhardt, Anke Doyon, Tobias Vinke, Anja Sander, Michael Henn, Ute Derichs, Rolf Beetz, Nikola Jeck, Bärbel Lange-Sperandio, Sabine Ponsel, Franziska Kusser, Barbara Uetz, Marcus Benz, Silke Schmidt, Christina Huppertz-Kessler, Birgitta Kranz, Andrea Titieni, Donald Wurm, Heinz E. Leichter, Martin Bald, Heiko Billing, Marwa M. Nabhan, Luis Enrique Lara, Fotios Papachristou, Francesco Emma, Rimante Cerkauskiene, Karolis Azukaitis, Anna Wasilewska, Irena Balasz-Chmielewska, Monika Miklaszewska, Marcin Tkaczyk, Przemyslaw Sikora, Marcin Zaniew, Ania Niemirska, Jolanta Antoniewicz, Justyna Lesiak, Alberto Caldas Afonso, Ana Teixeira, Gordana Milosevski-Lomic, Dusan Paripović, Amira Peco-Antic, Svetlana Papizh, Aysun Karabay Bayazit, Ali Anarat, Alper Soylu, Salih Kavukcu, Cengiz Candan, Salim Caliskan, Nur Canpolat, Sevinc Emre, Harika Alpay, Nurver Akinci, Secil Conkar, Hakan M. Poyrazoglu, Ruhan Dusunsel, Çukurova Üniversitesi, Burgmaier, Kathrin, Kunzmann, Kevin, Ariceta, Gema, Bergmann, Carsten, Buescher, Anja Katrin, Burgmaier, Mathias, Dursun, Ismail, Duzova, Ali, Eid, Loai, Erger, Florian, Feldkoetter, Markus, Galiano, Matthias, Gessner, Michaela, Goebel, Heike, Gokce, Ibrahim, Haffner, Dieter, Hooman, Nakysa, Hoppe, Bernd, Jankauskiene, Augustina, Klaus, Guenter, Koenig, Jens, Litwin, Mieczyslaw, Massella, Laura, Mekahli, Djalila, Melek, Engin, Mir, Sevgi, Pape, Lars, Prikhodina, Larisa, Ranchin, Bruno, Schild, Raphael, Seeman, Tomas, Sever, Late, Shroff, Rukshana, Soliman, Neveen A., Stabouli, Stella, Stanczyk, Malgorzata, Tabel, Yilmaz, Taranta-Janusz, Katarzyna, Testa, Sara, Thumfart, Julia, Topaloglu, Rezan, Weber, Lutz Thorsten, Wicher, Dorota, Wuehl, Elke, Wygoda, Simone, Yilmaz, Alev, Zachwieja, Katarzyna, Zagozdzon, Ilona, Zerres, Klaus, Doetsch, Joerg, Schaefer, Franz, and Liebau, Max Christoph
- Subjects
Male ,0301 basic medicine ,Time Factors ,medicine.medical_treatment ,ARPKD ,Medizin ,030232 urology & nephrology ,PROTEIN ,Oligohydramnios ,Pediatrics ,PKHD1 MUTATIONS ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Prospective Studies ,ENCODES ,GENOTYPE-PHENOTYPE CORRELATIONS ,Obstetrics ,Hazard ratio ,Autosomal Recessive Polycystic Kidney Disease ,CLINICAL-EXPERIENCE ,Female ,Apgar score ,Life Sciences & Biomedicine ,renal replacement therapy ,medicine.medical_specialty ,GENETICS ,PKHD1 ,Risk Assessment ,Ultrasonography, Prenatal ,03 medical and health sciences ,Renal Dialysis ,medicine ,Humans ,Renal replacement therapy ,Dialysis ,Polycystic Kidney, Autosomal Recessive ,Retrospective Studies ,Science & Technology ,business.industry ,Infant, Newborn ,Infant ,Retrospective cohort study ,medicine.disease ,030104 developmental biology ,ciliopathy ,Pediatrics, Perinatology and Child Health ,business ,oligohydramnios ,Follow-Up Studies - Abstract
OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD. ispartof: JOURNAL OF PEDIATRICS vol:199 pages:22-+ ispartof: location:United States status: published
- Published
- 2018
41. Genetics in Nephrourology
- Author
-
Klaus Zerres, Miriam Elbracht, and Sabine Rudnik
- Published
- 2018
42. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients
- Author
-
Uwe Kornak, Janbernd Kirschner, Katja Eggermann, K von Au, Jan Senderek, Wolfgang Müller-Felber, M. von der Hagen, C. Bußmann, D. Tölle, Dagmar Wieczorek, Barbara Leube, Ulrike Schara, Miriam Elbracht, Klaus Zerres, and Sabine Rudnik-Schöneborn
- Subjects
0301 basic medicine ,Genetics ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Genetic data ,Diagnostic algorithms ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Gene duplication ,Mutation (genetic algorithm) ,medicine ,Mutation detection ,Clinical severity ,Genetic diagnosis ,030217 neurology & neurosurgery ,Genetics (clinical) ,Genetic testing - Abstract
We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot-Marie-Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly 40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.
- Published
- 2015
43. Nicht-invasive genetische Pränataldiagnostik – eine gesamtgesellschaftliche Herausforderung
- Author
-
Klaus Zerres
- Subjects
Maternity and Midwifery ,Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology - Abstract
Nicht-invasive genetische Pranataltests erlauben heute mit hoher Zuverlassigkeit die Identifizierung von Schwangerschaften mit kindlichen Aneuploidien. Durch die prinzipielle Verfugbarkeit der Tests fur alle Schwangeren wirft das Testangebot eine Vielzahl ethischer Fragen auf, deren Beantwortung nur in einen gesamtgesellschaftlichen Diskurs moglich ist.
- Published
- 2015
44. Alcohol Consumption in HealthyOPRM1G Allele Carriers and Its Association with Impulsive Behavior
- Author
-
Ingo Vernaleken, Thomas Eggermann, Christoph Fehr, Oliver Tüscher, Klaus Zerres, Murat Sariyar, and Philippe Pfeifer
- Subjects
Adult ,Male ,medicine.medical_specialty ,Alcohol Drinking ,Genotype ,Perseveration ,Receptors, Opioid, mu ,Poison control ,Single-nucleotide polymorphism ,Impulsivity ,Polymorphism, Single Nucleotide ,Young Adult ,Polymorphism (computer science) ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Allele ,Psychiatry ,Alleles ,Alcohol Use Disorders Identification Test ,General Medicine ,Middle Aged ,Impulsive Behavior ,medicine.symptom ,Psychology ,Clinical psychology - Abstract
AIMS: A link between alcohol use disorders (AUD) and impulsivity is well established. As there is evidence for the heritability of AUD, the investigation of the underlying genetic disposition for both conditions is an important issue. An association between AUD and a coding single nucleotide polymorphism (SNP) (rs1799971 encoding an Asn40Asp amino acid substitution, A118G) within the µ-opioid receptor 1 gene (OPRM1) has been reported. Therefore we tested the association between the OPRM1 A118G polymorphism and drinking as well as impulsive behavior in social drinkers. METHODS: A total of 214 healthy male social drinkers were recruited. Each participant was genotyped for the OPRM1 A118G variant. Alcohol use was assessed with items of the Alcohol Use Disorders Identification Test (AUDIT). Impulsivity was assessed using the UPPS impulsive behavior scale. For statistical analyses, we considered correlations, t-tests and ordinal regression models using SPSS V21. RESULTS: In total, 49 out of 214 participants were carriers of the OPRM1 118G allele. On average the OPRM1 118G carriers showed a slightly higher propensity for alcohol drinking. Higher drinking frequency among the G allele carriers was linked with higher urgency and perseveration subscores of impulsivity. CONCLUSION: Our results suggest a genetically influenced higher propensity for alcohol drinking among social drinkers carrying the 118G allele of the OPRM1 gene. The positive correlation between urgency and a higher drinking frequency among the OPRM1 118G hint towards a functional meaning of the opioid system in the regulation of impulsivity. Language: en
- Published
- 2015
45. Neither maternal nor fetal mutation (E474Q) in the α-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome
- Author
-
Klaus Zerres, Ines Ahillen, Brigitte Leeners, Werner Rath, S Kuse, P Neumaier-Wagner, Sabine Rudnik-Schoeneborn, S. Mütze, Thomas Eggermann, University of Zurich, and Mütze, Sabine
- Subjects
HELLP Syndrome ,Heterozygote ,medicine.medical_specialty ,HELLP syndrome ,610 Medicine & health ,Compound heterozygosity ,142-005 142-005 ,Loss of heterozygosity ,Fetus ,Pregnancy ,Internal medicine ,medicine ,Humans ,2735 Pediatrics, Perinatology and Child Health ,business.industry ,3-Hydroxyacyl CoA Dehydrogenases ,Obstetrics and Gynecology ,Chromosome ,2729 Obstetrics and Gynecology ,medicine.disease ,Endocrinology ,Amino Acid Substitution ,Mutation ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Female ,Restriction fragment length polymorphism ,business - Abstract
OBJECTIVE: An association between maternal HELLP syndrome and fetal long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been proposed. LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria. Whereas about 75% of LCHAD-deficient patients carry a G-to-C mutation at nucleotide position 1528 (Glu474Gln, E474Q) on both chromosomes, compound heterozygosity for E474Q on one chromosome and a second different LCHAD mutation on the other can be observed in up to 25% of LCHAD-deficiency cases; only very few patients carry two mutations different from E474Q. Genetic analysis of the mother alone is insufficient in case of compound heterozygosity. Since information on the fetal carrier status of the E474Q mutation in maternal HELLP syndrome is rare, we investigated the frequency of the E474Q mutation in families where the mother had HELLP syndrome. METHODS: The occurrence of the E474Q mutation was analyzed by PCR and RFLP in 103 mothers with HELLP syndrome, in 82 children of affected pregnancies and in 21 fathers in families where fetal DNA was not available. In addition, 103 control women with only uncomplicated pregnancies were investigated. RESULTS: The mutation E474Q was not detected in the study population. CONCLUSION: Neither maternal nor fetal heterozygosity for the E474Q mutation is a relevant factor of HELLP syndrome.
- Published
- 2017
46. Mutations in DZIP1L, which encodes a ciliary transition zone protein, cause autosomal recessive polycystic kidney disease
- Author
-
Carol Wicking, Milan Hiersche, Björn Hartleben, Walter Hunziker, Hao Lu, Peter Papathanasiou, Robert Tunningley, Shubha Vij, Friedhelm Hildebrandt, Valeska Frank, Heon Yung Gee, Graham D. Wright, Carsten Bergmann, Nadina Ortiz-Brüchle, Sudipto Roy, Klaus Zerres, Maria C. Rondón Galeano, Andrew C. Perkins, Nadescha Hilger, Melissa H. Little, Edgar A. Otto, Udo Vester, Daniel Epting, Elisabeth Ott, Elke Wühl, P. Jaya Kausalya, Vicki Metzis, Geraldine Kaeslin, Andrew D. Courtney, Belinda Whittle, Shang Yew Tay, Carina Kramer, and Steffen Neuber
- Subjects
0301 basic medicine ,Male ,Embryo, Nonmammalian ,TRPP Cation Channels ,Genetic Linkage ,Medizin ,Consanguinity ,Biology ,urologic and male genital diseases ,Article ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,Polycystic kidney disease ,medicine ,Basal body ,Animals ,Humans ,Abnormalities, Multiple ,Cilia ,Zebrafish ,Adaptor Proteins, Signal Transducing ,Centrioles ,Polycystic Kidney, Autosomal Recessive ,Ciliary transition zone ,Membrane Proteins ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,female genital diseases and pregnancy complications ,Autosomal Recessive Polycystic Kidney Disease ,Transport protein ,Pedigree ,Mice, Inbred C57BL ,Disease Models, Animal ,Protein Transport ,030104 developmental biology ,Gene Knockdown Techniques ,Female ,Chromosomes, Human, Pair 3 ,030217 neurology & neurosurgery ,Septins - Abstract
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.
- Published
- 2017
47. Uniparental disomy as an unexpected cause of Meckel-Gruber syndrome: report of a case
- Author
-
Klaus Zerres, Nadia Ortiz Bruechle, Thomas Eggermann, Peter Steuernagel, Ingo Kurth, and Cordula Knopp
- Subjects
0301 basic medicine ,Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,TMEM67 ,Genetic counseling ,DNA Mutational Analysis ,030105 genetics & heredity ,Biology ,Ciliopathies ,Joubert syndrome ,Ultrasonography, Prenatal ,03 medical and health sciences ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Genetic Testing ,Meckel-Gruber Syndrome ,Encephalocele ,Genetics ,Polycystic Kidney Diseases ,Homozygote ,Membrane Proteins ,Abortion, Induced ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,Ciliopathy ,Fetal Diseases ,030104 developmental biology ,Nephrology ,Karyotyping ,Pediatrics, Perinatology and Child Health ,Mutation ,Female ,Retinitis Pigmentosa ,SNP array ,Chromosomes, Human, Pair 8 ,Ciliary Motility Disorders - Abstract
Meckel–Gruber syndrome (MKS, OMIM #607361) is a rare pre- or perinatal lethal autosomal recessive ciliopathy caused by mutations in at least 12 known genes. It has a clinical and genetic overlap with other viable ciliopathies, especially Joubert syndrome and Joubert syndrome-related disorders. MKS is characterized by multicystic kidney dysplasia, central nervous system malformations (usually occipital encephalocele), ductal plate malformation of the liver, and postaxial polydactyly. We identified a homozygous mutation in TMEM67 (MKS3) in a fetus affected by MKS; however, only the mother was a carrier of the respective mutation. Genotyping with polymorphic microsatellite markers and single nucleotide polymorphism (SNP) array revealed a maternal uniparental disomy (UPD) of the entire chromosome 8 (upd(8)mat), harboring TMEM67. This is the first reported case of UPD as a cause of MKS. The possible underlying mechanisms for uniparental disomy (UPD) are reviewed. Even if rare, awareness of UPD and comprehensive work-up in the case of unexpected homozygosity for a recessive mutation is essential for accurate genetic counseling and assessment of the risk of recurrence.
- Published
- 2017
48. Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations
- Author
-
Jörg Dötsch, Kathrin Ebner, Bernhard Schermer, Friederike Koerber, Max C. Liebau, Thomas Benzing, Nadina Ortiz-Bruechle, Lutz T. Weber, Bodo B. Beck, Claudia Dafinger, and Klaus Zerres
- Subjects
Pathology ,medicine.medical_specialty ,Genotype ,medicine.medical_treatment ,DNA Mutational Analysis ,030232 urology & nephrology ,Fibrocystin ,Receptors, Cell Surface ,Kidney ,End stage renal disease ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Polycystic kidney disease ,medicine ,Missense mutation ,Humans ,Point Mutation ,Renal replacement therapy ,Genetic Testing ,Polycystic Kidney, Autosomal Recessive ,Genetics ,Hyperplasia ,biology ,business.industry ,Infant, Newborn ,Exons ,Infant, Low Birth Weight ,medicine.disease ,Magnetic Resonance Imaging ,Autosomal Recessive Polycystic Kidney Disease ,Introns ,Phenotype ,Nephrology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Mutation ,biology.protein ,Kidney Failure, Chronic ,Female ,business ,Infant, Premature ,Hepatomegaly - Abstract
Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype–phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.
- Published
- 2017
49. 5.4 Genetische Ursachen des unerfüllten Kinderwunsches
- Author
-
Klaus Zerres, Jan Murken, Tiemo Grimm, and Elke Holinski-Feder
- Published
- 2017
50. 4.5 Genetischer Abstammungs- und Identifikationsnachweis
- Author
-
Jan Murken, Tiemo Grimm, Klaus Zerres, and Elke Holinski-Feder
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.