Allison M Matthews1,2,3, Ingrid Blydt-Hansen2, Basmah Al-Jabri4,5, John Andersen4,6, Maja Tarailo-Graovac7, Magda Price1,2,3, Katherine Selby2,8, Michelle Demos2,8, Mary Connolly2,8, Britt Drögemoller2, Casper Shyr2, Jill Mwenifumbo1,2, Alison M Elliott1,2, Jessica Lee2, Aisha Ghani2, Sylvia Stöckler2,8, Ramona Salvarinova2,8, Hilary Vallance3,9, Graham Sinclair2,9, Colin J Ross2,10, Wyeth W Wasserman1,2,3, Margaret L McKinnon1,2, Gabriella A Horvath2,8, Helly Goez4, Clara D van Karnebeek11,12,13,14. 1. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. 2. BC Children's Hospital Research Institute, Vancouver, BC, Canada. 3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada. 4. Department of Pediatrics, University of Alberta, Edmonton, AB, Canada. 5. Department of Pediatrics, King Abdul Aziz University, Jeddah, Saudi Arabia. 6. Department of Physical Medicine & Rehabilitation, University of Alberta, Edmonton, AB, Canada. 7. Departments of Biochemistry, Molecular Biology, and Medical Genetics, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada. 8. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. 9. Department of Pathology and Laboratory medicine, University of British Columbia, Vancouver, BC, Canada. 10. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. 11. BC Children's Hospital Research Institute, Vancouver, BC, Canada. c.d.vankarnebeek@amc.uva.nl. 12. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada. c.d.vankarnebeek@amc.uva.nl. 13. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. c.d.vankarnebeek@amc.uva.nl. 14. Departments of Pediatrics and Clinical Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands. c.d.vankarnebeek@amc.uva.nl.
Abstract
PURPOSE: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP). METHODS: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis. RESULTS: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%). CONCLUSION: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.
PURPOSE: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP). METHODS: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis. RESULTS: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%). CONCLUSION: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.
Authors: Sara A Lewis; Sheetal Shetty; Bryce A Wilson; Aris J Huang; Sheng Chih Jin; Hayley Smithers-Sheedy; Michael C Fahey; Michael C Kruer Journal: Front Neurol Date: 2021-01-21 Impact factor: 4.003
Authors: Diane Beysen; Chania De Cordt; Charlotte Dielman; Benson Ogunjimi; Julie Dandelooy; Edwin Reyniers; Katrien Janssens; Marije M E Meuwissen Journal: Front Neurol Date: 2021-04-22 Impact factor: 4.003
Authors: Maja Tarailo-Graovac; Gabriella A Horvath; Clara D van Karnebeek; Ingrid Blydt-Hansen; Allison M Matthews; Vladimir Avramovic; Magda Price; Britt Drogemoller; Casper Shyr; Jessica Lee; Jill Mwenifumbo; Aisha Ghani; Sylvia Stockler; Jan M Friedman; Anna Lehman; Colin J Ross; Wyeth W Wasserman Journal: Neurogenetics Date: 2021-07-02 Impact factor: 2.660
Authors: Halie J May; Jennifer A Fasheun; Jennifer M Bain; Evan H Baugh; Louise E Bier; Anya Revah-Politi; David P Roye; David B Goldstein; Jason B Carmel Journal: Dev Med Child Neurol Date: 2021-06-10 Impact factor: 4.864