Oral Presentation GENEMAPPERS 2026

Genome sequencing for developmental and epileptic encephalopathies: detecting variants beyond coding regions boosts diagnostic yield (#35)

Jacob E Munro 1 2 , Harshini Thiyagarajah 3 , Mark F Bennett 2 3 , Annie Chiu 3 , Amy Schneider 3 , Caitlin Bennett 3 , Talia Allan 3 , Nico Lieffering 3 , Tom Witkowski 3 , Rebekah Harris 3 , Joshua Reid 3 , Neblina Sikta 3 , Sian Macdonald 3 , Lucy Coulter 3 , Michelle Dang 3 , Piero Perucca 3 , Samuel F Berkovic 3 , Christy W LaFlamme 4 , Heather C Mefford 4 , Melanie Bahlo 1 2 , Ingrid E Scheffer 3 5 , Michael S Hildebrand 3 5
  1. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  2. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  3. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria
  4. Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, United States
  5. Neuroscience Group, Murdoch Children’s Research Institute, Parkville, Victoria

PURPOSE: The majority of developmental and epileptic encephalopathies (DEEs) have a monogenic aetiology. Despite this, routine clinical genetic testing is nondiagnostic for half of DEE patients. We investigated if diagnostic yield would increase in a large cohort of individuals with unsolved DEEs by applying genome sequencing along with enhanced variant analyses outside of coding regions.

METHODS: Genome sequencing was performed for 242 participants with DEEs negative on prior genetic testing. We interrogated single nucleotide variants (SNVs), indels, and structural variants in both established and candidate DEE genes. All variants of interest were reviewed, classified, and validated by a multidisciplinary team.

RESULTS: A molecular diagnosis was found for 33/242 (13.6%) participants. The identified pathogenic or likely pathogenic variants comprised 26 SNVs and indels within coding regions, 6 structural variants affecting a single gene, and 5 SNVs and indels in introns or non-coding genes. Variants of uncertain significance were detected in a further 9/242 (3.7%) participants.

CONCLUSION: Genetic diagnostic yield for individuals with unsolved DEEs increased on genome sequencing analysis. This increase reflects both the identification of structural and non-coding variants not detectable on exome or gene panel analysis, and the detection of variants in genes newly associated with DEEs.