Gunelson Anna M, Kim Kwang-Soo, Steigerwald Connolly G, Segal Devorah, Abreu Nicolas J, Yi Jason J
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10016, USA.
J Hum Genet. 2025 May 2. doi: 10.1038/s10038-025-01343-z.
The loss of maternal UBE3A causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel UBE3A variant that is not present in two neurotypical siblings. The UBE3A variant was confirmed to be maternally inherited, and the affected individuals exhibited early global developmental delay, ongoing learning difficulties, and autistic features. Their phenotypes were inconsistent with Angelman syndrome. Biochemical characterization showed the UBE3A variant causes a dramatic increase in the activity of the UBE3A enzyme, suggesting that a gain in UBE3A activity is the driver of neurodevelopmental disease. Our observations document an emerging class of neurodevelopmental disorders caused by gain-of-function mutations in UBE3A.
母体UBE3A的缺失会导致天使综合征，而其复制则与一种异质性神经发育障碍有关。在此，我们描述了两名受影响的兄弟，他们拥有一种新型的UBE3A变体，而两个神经典型的兄弟姐妹中不存在这种变体。该UBE3A变体经证实是母系遗传的，受影响个体表现出早期全面发育迟缓、持续的学习困难和自闭症特征。他们的表型与天使综合征不一致。生化特征表明，该UBE3A变体导致UBE3A酶的活性显著增加，这表明UBE3A活性的增加是神经发育疾病的驱动因素。我们的观察记录了一类由UBE3A功能获得性突变引起的新兴神经发育障碍。
