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Identification of novel autosomal genes causing mental retardation

English title Identification of novel autosomal genes causing mental retardation
Applicant Rauch Anita
Number 135669
Funding scheme Project funding (Div. I-III)
Research institution Institut für Medizinische Genetik Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Genetics
Start/End 01.01.2012 - 31.12.2014
Approved amount 468'000.00
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All Disciplines (2)

Discipline
Genetics
Paediatrics

Keywords (4)

Mental retardation; Gene identification; Genotype-Phenotype correlation; Ultra-high-throughput sequencing

Lay Summary (German)

Lead
Lay summary

Die Begabung eines gesunden Kindes kann sehr unterschiedliche Stärken und Schwächen zeigen, jedoch weisen 2-3% der Kinder eine so starke Einschränkung der intellektuellen, motorischen oder sozialen Fähigkeiten auf, dass trotz Förderung ein selbstständiges Leben auch im Erwachsenenalter nicht möglich ist. Obwohl verschiedene Ursachen wie zum Beispiel eine vorgeburtliche Infektion in Frage kommen, spielen in hochentwickelten Ländern wie der Schweiz bei der Entstehung solcher neurokognitiven Entwicklungsstörungen vor allem genetische Schäden eine Rolle. Diese genetischen Schäden treten in den allermeisten Fällen ohne Vorwarnung bei Kindern gesunder Eltern und Familien auf, so dass es Jeden treffen kann. Obwohl mittlerweile über 400 verschiedene genetische Krankheitsbilder als Ursache von Entwicklungsstörungen aufgeklärt werden konnten, bleibt die genaue Erkrankung bei einem Grossteil der betroffenen Kinder heute noch unklar. Die Kenntnis der genauen Krankheitsursache ist aber Voraussetzung dafür, den Eltern Klarheit über den Vererbungsmechanismus zu verschaffen und die Behandlung der Kinder mittel- bis langfristig zu verbessern. So wird zum Beispiel derzeit in grossen internationalen Studien ein neuartiges Medikament getestet, welches nach bisherigen Erkenntnissen in der Lage zu sein scheint, bei Menschen mit Fragilem X Syndrom, einer relativ häufigen Ursache von geistiger Behinderung und Verhaltensstörungen, die Krankheit durch eine gezielte Beeinflussung der genetisch gestörten Prozesse abzuschwächen.

Ziel dieses Forschungsprojektes ist es daher, bislang unbekannte Genschäden als Ursachen von neurokognitiven Entwicklungsstörungen aufzuklären. Hierbei kommen neueste genetische Analysetechniken gepaart mit einer sorgfältigen klinischen Beobachtung zum Einsatz. Durch die Aufklärung und Charakterisierung neuer Krankheitsbilder auf molekularer und klinischer Ebene sollen neue Ansatzpunkte für eine verbesserte Diagnostik und Behandlung der Betroffenen geschaffen werden.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The clinical significance of small copy number variants in neurodevelopmental disorders.
Asadollahi Reza, Oneda Beatrice, Joset Pascal, Azzarello-Burri Silvia, Bartholdi Deborah, Steindl Katharina, Vincent Marie, Cobilanschi Joana, Sticht Heinrich, Baldinger Rosa, Reissmann Regina, Sudholt Irene, Thiel Christian T, Ekici Arif B, Reis André, Bijlsma Emilia K, Andrieux Joris, Dieux Anne, FitzPatrick David, Ritter Susanne, Baumer Alessandra, Latal Beatrice, Plecko Barbara, Jenni Oskar G, Rauch Anita (2014), The clinical significance of small copy number variants in neurodevelopmental disorders., in Journal of medical genetics, 51(10), 677-88.
Biallelic SEMA3A defects cause a novel type of syndromic short stature.
Hofmann Kristin, Zweier Markus, Sticht Heinrich, Zweier Christiane, Wittmann Wolfgang, Hoyer Juliane, Uebe Steffen, van Haeringen Arie, Thiel Christian T, Ekici Arif B, Reis André, Rauch Anita (2013), Biallelic SEMA3A defects cause a novel type of syndromic short stature., in American journal of medical genetics. Part A, 161A(11), 2880-9.
Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability.
Asadollahi Reza, Oneda Beatrice, Sheth Frenny, Azzarello-Burri Silvia, Baldinger Rosa, Joset Pascal, Latal Beatrice, Knirsch Walter, Desai Soaham, Baumer Alessandra, Houge Gunnar, Andrieux Joris, Rauch Anita (2013), Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability., in European journal of human genetics : EJHG, 21(10), 1100-4.
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.
Rauch Anita, Wieczorek Dagmar, Graf Elisabeth, Wieland Thomas, Endele Sabine, Schwarzmayr Thomas, Albrecht Beate, Bartholdi Deborah, Beygo Jasmin, Di Donato Nataliya, Dufke Andreas, Cremer Kirsten, Hempel Maja, Horn Denise, Hoyer Juliane, Joset Pascal, Röpke Albrecht, Moog Ute, Riess Angelika, Thiel Christian T, Tzschach Andreas, Wiesener Antje, Wohlleber Eva, Zweier Christiane, Ekici Arif B (2012), Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study., in Lancet (London, England), 380(9854), 1674-82.

Collaboration

Group / person Country
Types of collaboration
Prof. Esther Stoeckli, Institute of Molecular Life Sciences at the University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Decipher Consortium Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
German Mental Retardation Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Devision of child development at the Pediatric University Hospital Zürich Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Human Genetics in the Era of Translational Medicine Talk given at a conference Individual Genomes and Personalized Medicine 02.10.2015 Erlangen, Germany Rauch Anita;
Opening Symposium of the Center of Human Safety & Health and Genome Diagnostic Analysis Talk given at a conference Genetic Testing in Personalized Medicine 19.09.2015 Dubai, United Arab Emirates Rauch Anita;
European Dysmorphology Meeting Talk given at a conference KDM1A mutations in intellectual disability 09.09.2015 Le Bischenberg bei Strasburg, France Rauch Anita;
36th Annual David W. Smith Workshop on Malformations and Morphogenesis Talk given at a conference Clinical and experimental evidence establish a link between KIF7 and C5orf42-related ciliopathies 14.08.2015 St. Michaels, United States of America Rauch Anita;
Annual meeting of the Eurpean Society of Human Genetics Talk given at a conference NGS in diagnostics: Challenging example cases 06.06.2015 Glasgow, Great Britain and Northern Ireland Rauch Anita;
Manchester bianual Birth defects meeting Talk given at a conference Two novel entities with borderline IQ caused by 5p deletions 10.11.2014 Manchester, Great Britain and Northern Ireland Rauch Anita;
35th Annual David W. Smith Workshop on Malformations and Morphogenesis Talk given at a conference The significance of small copy number variants in neuro-developmental disorders 25.07.2014 Wisconsin, United States of America Rauch Anita;
3rd COURSE IN NEXT GENERATION SEQUENCING Talk given at a conference Exome diagnostics in intellectual disability 06.05.2014 Bertinoro di Romagna , Italy Rauch Anita;
Showcase: Swiss Programs at the RE(ACT) Congress 2014 Talk given at a conference Genomic studies in neurodevelopmental disorders 06.03.2014 Basel, Switzerland Rauch Anita;
39th Annual Conference of Indian Society of Human Genetics and International conference on Human Genetics Talk given at a conference Non‐syndromic sporadic intellectual disability: an exome sequencing study 23.01.2014 Ahmedabad, India Rauch Anita;
INCONTRO GRUPPO DI LAVORO GENETICA CLINICA Talk given at a conference DIAGNOSTIC APPROACH TO INTELLECTUAL DISABILITY 09.12.2013 Rom, Italy Rauch Anita;
JahreskongressesderDeutschenGesellschaftfürKinder-undJugendmedizin Talk given at a conference Range of genetic mutations associated with severe nonsyndromic sporadic intellectual disability: an exome sequencing study 02.09.2013 Düsseldorf, Germany Rauch Anita;
ZNZ Symposium 2013 Talk given at a conference Genetics of severe unspecific intellectual disability 13.08.2013 Zürich, Switzerland Rauch Anita;
COURSE IN NEXT GENERATION SEQUENCING Talk given at a conference Exome diagnostics in intellectual disability 17.05.2013 Bertinoro di Romagna , Italy Rauch Anita;
KLINISCH-BIOCHEMISCHES KOLLOQUIUM Individual talk Unraveling the Genetic Basis of Severe Mental Retardation with Exome Sequencing 06.05.2013 Zürich, Switzerland Rauch Anita;
Symposium Molekulare Diagnostik 2013 Talk given at a conference Entwicklungsstörungen und Intelligenzdefekte im Licht neuer gendiagnostischer Verfahren 28.02.2013 Zürich, Switzerland Rauch Anita;
Fortbildung Kontonsspital Frauenfeld Individual talk Neuigkeiten im Bereich der genetischen Methoden 04.12.2012 Frauenfeld, Switzerland Rauch Anita;
Forum Dialog Psychiatrie-Neurologie Talk given at a conference Neue genetische Diagnose-Verfahren und deren ethische Implikationen 01.11.2012 Zürich, Switzerland Rauch Anita;
Manchester Birth defects Meeting Talk given at a conference Exome sequencing in severe unspecific intellectual disability broadens phenotype of well- known disease entities 25.10.2012 Manchester, Great Britain and Northern Ireland Rauch Anita;
Jahrestagung der Deutschen Gesellschaft für Kinder-und Jugendmedizin Talk given at a conference Neue Untersuchungsmethoden des menschlichen Genoms 15.09.2012 Hamburg, Germany Rauch Anita;
23rd European Meeting on Dysmorphology Talk given at a conference Biallelic SEMA3A defects cause a novel type of syndromic short stature 07.09.2012 Le Bischenberg bei Strasburg, France Rauch Anita;
Kongress der Schweizerischen Union für Labormedizin (SULM) Talk given at a conference Next Generation Sequencing in der Diagnostik genetischer Erkrankungen 13.06.2012 Bern, Switzerland Rauch Anita;
Vortragsreihe Humangenetik Individual talk Genetik mentaler Retardierung im Zeitalter genomweiter Analysen 23.05.2012 Leipzig, Germany Rauch Anita;
Genomic Disorders 2012 Talk given at a conference Identification Of De Novo Variants In 51 Sporadic Patients With Unspecific Intellectual Disability And 20 Controls By Exome Sequencing 23.03.2012 Hinxton, Great Britain and Northern Ireland Rauch Anita;
React - INTERNATIONAL CONGRESS ON RESEARCH OF RARE AND ORPHAN DISEASES Talk given at a conference Towards a deeper understanding of intellectual disability disorders 01.03.2012 Basel, Switzerland Rauch Anita;
Symposium Humangenetik Talk given at a conference Genetik kognitiver Entwicklungsstörungen im Zeitalter genomweiter Analysen 23.02.2012 Hannover, Germany Rauch Anita;
Symposium Next Generation – Humangenetik im 21. Jahrhundert Talk given at a conference Molekulare Syndromologie: Klinische Genetik im Zeitalter genomweiter Analysen 07.02.2012 Hamburg, Germany Rauch Anita;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Rare Disease Action Forum Basel Talk 03.11.2015 Bern, Switzerland Rauch Anita;
59. Sitzung der Wirtschaftsdelegation der Stadt Zürich Talk 03.09.2015 Schlieren, Switzerland Rauch Anita;


Associated projects

Number Title Start Funding scheme
179547 Genetic causes and molecular mechanisms in severe intellectual disability 01.05.2018 Project funding (Div. I-III)
154238 Primary monogenic microcephalies: from genetics to pathophysiology and the clinic 01.10.2014 ERA-NET

Abstract

Mental retardation (MR) is defined as significant impairment in cognitive and adaptive functions with onset during childhood. It affects about 2-3% of the population and places a severe burden on the individual and the family. Although more than 400 genes are known to be involved in the etiology of mental retardation in humans, the etiology especially of the most common autosomal and clinically unspecific types remains elusive in the majority of cases. Many of the currently known MR-related genes are involved in brain development, neurogenesis and neuronal migration. More recently disturbance of synaptic organization and plasticity in MR has also been recognized. These findings raise the exciting question whether in the future we might be able to cure or at least alleviate some types of mental retardation through therapeutic intervention. Recent technological advancements such as next-generation sequencing have enabled a quantum leap in the possibilities of genome wide analysis for the identification of causative genes and pathomechanisms especially in sporadic disorders such as mental retardation, which were mainly intractable by classical genetic strategies.The aim of the proposed project is to systematically search for novel genes underlying autosomal, clinically unspecific mental retardation and to further elucidate the pathways involved as a prerequisite for the development of novel therapeutic approaches. To achieve this goal we will use the novel technique of ultra-high-throughput sequencing to identify novel disease genes in a clinically well characterized cohort of 120 sporadic and familial cases with mental retardation of unknown etiology. Findings will be validated with data from copy number profiling and SNP genotyping as well as mutational screening in a cohort of 1000 patients. This approach will allow identification of novel MR genes, enable genotype-phenotype correlation and improve diagnostic options and management strategies for patients. Further functional characterization of identified mutations and disease genes will increase our knowledge about human brain function and unveil novel targets for therapeutic intervention. This project thus will reveal significant new insights for medical practice as well as for our general understanding of the biology of human brain function.
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