Erdogan Esin Nur, Cheng Chi Vicky, Caraffi Stefano G, Ivanovski Ivan, Piatelli Gianluca, Errichiello Edoardo, Papavasiliou Antigone S, Vasileiou Georgia, Reis André, Prince Bradley, Hickey Scott E, Koboldt Daniel C, Schneider Michael C, Porrmann Joseph, Di Donato Nataliya, Leis Thomas, Perry M Scott, Humberson Jennifer, Rotenberg Joshua, Bakhtiari Somayeh, Magee Helen, Kheradmand Shaydah, Kruer Michael C, Swale Andrew, Weber Astrid, Landes Caren, Zuffardi Orsetta, Garavelli Livia, van Haeringen Arie, Ruivenkamp Claudia A L, Pauly Melissa, Au Ping Yee Billie, Dobyns William B, Aldinger Kimberly A
Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
Am J Med Genet A. 2025 May 3:e64093. doi: 10.1002/ajmg.a.64093.
Haploinsufficiency of AUTS2 is associated with a neurodevelopmental disorder characterized by intellectual disability, autistic features, and spasticity. AUTS2 protein interacts with p300, encoded by EP300, through the HX repeat domain of AUTS2, thereby activating transcription. We previously reported two de novo variants in the HX repeat domain of AUTS2. These variants disrupt the AUTS2-P300 interaction, resulting in a phenotype resembling Rubinstein-Taybi Syndrome (RSTS) associated with variants in EP300/CREBBP. Here, we expand beyond the initial clinical description to delineate the HX domain-associated phenotype and compare it to the AUTS2-haploinsufficient phenotype. We reviewed clinical data, photographs, and neuroimaging studies to examine genotype-phenotype relationships. Our review of 80 individuals included 14 individuals we present here and 66 individuals with AUTS2 variants presented in the literature. The clinical features for individuals with variants in the HX repeat domain include severe intellectual disability, severe language disability, distinct craniofacial and skeletal dysmorphic features, and neuroimaging findings. Facial dysmorphisms include wide and prominent nasal bridges with complex nasal shapes and dysmorphic eyebrows. Dysmorphisms include digit anomalies: Symphalangism and hypoplasia of distal phalanges, exclusive to the HX domain variant group. Cerebellar anomalies not seen with other AUTS2 variants are seen within this group. Our report delineates a distinct and severe clinical phenotype associated with variants in the AUTS2 HX domain, including an in-depth comparison with the AUTS2 haploinsufficiency phenotype features.
AUTS2单倍剂量不足与一种神经发育障碍相关，其特征为智力残疾、自闭症特征和痉挛。AUTS2蛋白通过AUTS2的HX重复结构域与由EP300编码的p300相互作用，从而激活转录。我们之前报道了AUTS2的HX重复结构域中的两个新生变体。这些变体破坏了AUTS2-P300相互作用，导致了一种类似于与EP300/CREBBP变体相关的鲁宾斯坦-泰比综合征（RSTS）的表型。在这里，我们超越了最初的临床描述，以描绘与HX结构域相关的表型，并将其与AUTS2单倍剂量不足的表型进行比较。我们回顾了临床数据、照片和神经影像学研究，以检查基因型-表型关系。我们对80名个体的回顾包括我们在此呈现的14名个体和文献中报道的66名具有AUTS2变体的个体。HX重复结构域变体个体的临床特征包括严重智力残疾、严重语言残疾、独特的颅面和骨骼畸形特征以及神经影像学表现。面部畸形包括鼻梁宽阔突出、鼻形复杂以及眉形异常。畸形包括手指异常：关节粘连和远端指骨发育不全，这是HX结构域变体组所特有的。在该组中可见其他AUTS2变体未见的小脑异常。我们的报告描绘了一种与AUTS2 HX结构域变体相关的独特且严重的临床表型，包括与AUTS2单倍剂量不足表型特征的深入比较。
