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A novel intronic variant in UBE3A identified by genome sequencing in a patient with an atypical presentation of Angelman syndrome

2020; Wiley; Volume: 182; Issue: 9 Linguagem: Inglês

10.1002/ajmg.a.61740

1552-4833

Meredith Curtis, Danielle Baribeau, Susan Walker, Melissa Carter, Gregory Costain, Sylvia Lamoureux, Eriskay Liston, Christian R. Marshall, Miriam S. Reuter, Meaghan Snell, J Summers, Jacob Vorstman, Rebekah Jobling,

Genomics and Rare Diseases

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.