Kavitha Kothur1, Katherine Holman2, Elizabeth Farnsworth2, Gladys Ho3, Michelle Lorentzos1, Christopher Troedson4, Sachin Gupta4, Richard Webster1, Peter G Procopis5, Manoj P Menezes6, Jayne Antony4, Simone Ardern-Holmes1, Russell C Dale1, John Christodoulou7, Deepak Gill1, Bruce Bennetts8. 1. TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, The University of Sydney, Sydney, NSW, Australia. 2. Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia. 3. Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child & Adolescent Health; Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia. 4. TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia. 5. TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Paediatric and Child health, Camperdown, The University of Sydney, Sydney, Australia. 6. TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, The University of Sydney, Sydney, NSW, Australia; Paediatric and Child health, Camperdown, The University of Sydney, Sydney, Australia. 7. Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute and Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia. 8. Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child & Adolescent Health; Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia. Electronic address: bruce.bennetts@health.nsw.gov.au.
Abstract
PURPOSE: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants. RESULTS: The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants. CONCLUSION: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.
PURPOSE: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants. RESULTS: The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants. CONCLUSION: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.
Authors: Heather E Olson; Scott T Demarest; Elia M Pestana-Knight; Lindsay C Swanson; Sumaiya Iqbal; Dennis Lal; Helen Leonard; J Helen Cross; Orrin Devinsky; Tim A Benke Journal: Pediatr Neurol Date: 2019-02-23 Impact factor: 3.372
Authors: Scott Demarest; Elia M Pestana-Knight; Heather E Olson; Jenny Downs; Eric D Marsh; Walter E Kaufmann; Carol-Anne Partridge; Helen Leonard; Femida Gwadry-Sridhar; Katheryn Elibri Frame; J Helen Cross; Richard F M Chin; Sumit Parikh; Axel Panzer; Judith Weisenberg; Karen Utley; Amanda Jaksha; Sam Amin; Omar Khwaja; Orrin Devinsky; Jeffery L Neul; Alan K Percy; Tim A Benke Journal: Pediatr Neurol Date: 2019-03-27 Impact factor: 3.372
Authors: Scott T Demarest; Heather E Olson; Angela Moss; Elia Pestana-Knight; Xiaoming Zhang; Sumit Parikh; Lindsay C Swanson; Katherine D Riley; Grace A Bazin; Katie Angione; Lisa-Marie Niestroj; Dennis Lal; Elizabeth Juarez-Colunga; Tim A Benke Journal: Epilepsia Date: 2019-07-16 Impact factor: 5.864
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