Authors :
Jacob Munro, BS – Genetics and Gene Regulation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
Harshini Thiyagarajah, BS – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Mark Bennett, PhD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Victoria, Australia
Annie Ting-Gee Chiu, MBBS, FHKCPaed – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Amy Schneider, MGenCouns – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Caitlin Bennett, BS – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Talia Allan, BS – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Nico Lieffering, BBmedSc (Hons) – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Tom Witkowski, BSc (Hons) – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Sian Macdonald, MSc – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Piero Perucca, MD, PhD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Samuel Berkovic, MD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
Christy LaFlamme, MSc – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Soham Sengupta, PhD – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Heather Mefford, MD, PhD – Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Melanie Bahlo, PhD – Genetics and Gene Regulation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
Ingrid Scheffer, AO MBBS PhD FRACP FAES FAA FRS – Epilepsy Research Centre and Royal Children’s Hospital, The University of Melbourne, Austin Health, Florey and Murdoch Children’s Research Institutes
Presenting Author: Michael Hildebrand, PhD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia; Neuroscience Group, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
Rationale:
Many individuals with developmental and epileptic encephalopathies (DEEs) have a monogenic aetiology. Despite this, 50% individuals are negative on standard clinical genetic testing. We investigated whether we could increase the genetic diagnostic yield in a cohort of individuals with unsolved DEEs using genome sequencing to detect pathogenic variants beyond coding regions.Methods:
Genome sequencing was performed on 234 participants with genetically undiagnosed DEEs who were unsolved on prior genetic testing. We interrogated short variants (single nucleotide variants and indels) and structural variants in both established and candidate DEE genes. Candidate variants were reviewed, classified, and validated by a multidisciplinary team of clinical, genetic, and bioinformatic experts.Results:
A causative variant was identified in 27/234 (11.4%) individuals. Pathogenic or likely pathogenic variants comprised 17 short variants in coding regions, five short variants in non-coding regions, and six structural variants, including one compound heterozygous case involving both a short and a structural variant. These variants were present in 23 different genes, with two genes (RNU2-2 and NEXMIF) with variants in three unrelated individuals each. A further 12/234 (5.1%) individuals harboured variants of uncertain significance warranting further investigation.Conclusions:
Our findings increased the yield of genetic diagnosis beyond 60% in individuals with DEEs by applying genome sequencing to unsolved cases. Detection and interpretation of structural and non-coding variants, commonly overlooked on standard clinical testing, promises to improve clinical diagnosis with implications for precision treatments in the future. Funding:
Medical Research Future Fund Australia, National Health and Medical Research Australia