Precision diagnosis for the remaining 50% of unsolved developmental and epileptic encephalopathies

Summary Our Developmental and Epileptic Encephalopathies Research (DEER) program aims to improve the genetic yield to above 70% for patients with DEEs. Our large cohort of 400 unsolved patients will DEEs, and 200 more to be recruited, combined with extensive preliminary data in genetic diagnosis, gene discovery and genotype-phenotype correlations for DEEs assure success in increasing diagnostic yield, and novel discoveries, during this project. The latest molecular approaches to find novel genetic cause underpinning the “hidden genetics” of DEEs at the germline and somatic level to provide deep insights into the genetic architecture of these diseases.

Project Details

Our Developmental and Epileptic Encephalopathies Research (DEER) program aims to improve the genetic yield to above 70% for patients with DEEs. Patients with DEEs typically have frequent, uncontrolled seizures and multiple, often severe seizure types. An ‘epileptic encephalopathy’ is defined by frequent epileptic activity on the electroencephalogram (EEG) that adversely impacts learning and behaviour and causes developmental slowing and regression. It is usually associated with severe to profound (IQ < 40) and a wide range of comorbidities, including psychiatric, such as autism spectrum disorder (ASD), sleep, gastrointestinal and gait disorders. Mortality of the DEEs is high, with ~20% dying by 20 years. If onset is in the newborn period, 53% of infants die by 2 years.

Our large cohort of 400 unsolved patients with DEEs, and 200 more to be recruited during the period of these grants, combined with extensive preliminary data in genetic diagnosis, gene discovery and genotype-phenotype correlations for DEEs assure success in increasing diagnostic yield, and novel discoveries, during this project. The latest molecular approaches to find novel genetic cause underpinning the “hidden genetics” of DEEs at the germline and somatic level to provide deep insights into the genetic architecture of these diseases.

Aims :

1. To analyse existing exome sequencing data from unsolved patients with DEEs for variants in known and novel DEE genes for genetic diagnosis.
2. To complete genome sequencing on unsolved patients with DEEs who have had previous genetic testing that was unrevealing to increase diagnostic yield and find new genes.
3. To perform high depth gene panel or exome sequencing, or sensitive droplet digital PCR, to detect variants in unsolved DEE patients with suspected somatic or parental mosaicism.
4. To conduct functional assays using patient-derived cells for a subset of patients with DEEs solved in Aims 1-3 with defects in synaptic proteins.
5. To correlate phenotypes of patients with genetic findings in Aims 1-4.

Methodology :

Application of a variety of current and newly developed genomic testing technologies to patients and families with DEEs and blood, brain, CSF and other tissues available to test for causative mutations.

This project provides the exceptional opportunity to work in an a large multidisciplinary clinical and laboratory research team with extensive clinical research and discovery science expertise. In addition to clinical experience and laboratory techniques, the development of project management, sample coordination and communication skills will be fostered.