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<p>The loss of maternal <i>UBE3A</i> causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel <i>UBE3A</i><sup>L734S</sup> variant that is not present in two neurotypical siblings. The <i>UBE3A</i><sup>L734S</sup> 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 <i>UBE3A</i><sup>L734S</sup> 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 <i>UBE3A</i>.</p>

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Autism and intellectual disability due to a novel gain-of-function mutation in UBE3A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月2日

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  • Anna M. Gunelson,
  • Kwang-Soo Kim,
  • Connolly G. Steigerwald,
  • Devorah Segal,
  • Nicolas J. Abreu,
  • Jason J. Yi

摘要

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 UBE3AL734S variant that is not present in two neurotypical siblings. The UBE3AL734S 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 UBE3AL734S 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.