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A novel intronic variant in UBE3A identified by genome sequencing in a patient with an atypical presentation of Angelman syndrome |
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| Authors: | Meredith Curtis Danielle Baribeau Susan Walker Melissa Carter Gregory Costain Sylvia Lamoureux Eriskay Liston Christian R Marshall Miriam S Reuter Meaghan Snell Jane Summers Jacob Vorstman Rebekah K Jobling |
| Institution: | 1. Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada;2. Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada;3. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada;4. Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;5. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada;6. Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada;7. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;8. CGEn, The Hospital for Sick Children, Toronto, Ontario, Canada;9. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada;10. Rebekah K. Jobling, 555 University Avenue, Toronto, ON M5G 1X8, Canada. |
| Abstract: | Angelman syndrome (AS) is a genetic neurodevelopmental disorder caused by loss or deficient expression of UBE3A on the maternally inherited allele. In 10–15% of individuals with a clinical diagnosis of AS, a molecular diagnosis cannot be established with conventional testing. We describe a 13‐year‐old male with an atypical presentation of AS, who was found to have a novel, maternally inherited, intronic variant in UBE3A (c.3‐12T>A) using genome sequencing (GS). Targeted sequencing of RNA isolated from blood confirmed the creation of a new acceptor splice site. These GS results ended a six‐year diagnostic odyssey and revealed a 50% recurrence risk for the unaffected parents. This case illustrates a previously unreported splicing variant causing AS. Intronic variants identifiable by GS may account for a proportion of individuals who are suspected of having well‐known genetic disorders despite negative prior genetic testing. |
| Keywords: | Angelman syndrome genetic counseling genome sequencing intronic UBE3A |