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