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<p> <?tk 2?><i>ANKRD17</i> has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous <i>ANKRD17</i> variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the <i>ANKRD17</i> gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C &gt; T (p.Arg418*) variation in <i>ANKRD17</i>. Our study highlighted in mouse models an association between <i>Ankrd17</i> haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following <i>Ankrd17</i> knockdown. These results expand the genetic and phenotypic spectrum of <i>ANKRD17</i>-related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of <i>ANKRD17</i>-related ID and ASD.</p>

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Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • Dan Xia,
  • Yuanyuan Xu,
  • Zhanwen He,
  • Rui Chen,
  • Xiaoqin Xiao,
  • Xiaojuan Li,
  • Kewen Deng,
  • Shuyun Deng,
  • Lina Zhang,
  • Jieming Zhang,
  • Xiaofang Peng,
  • Zhe Meng,
  • Ruohao Wu,
  • Dilong Wang,
  • Zulin Liu,
  • Hui Chen,
  • Lu Li,
  • Liyang Liang

摘要

ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17. Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17-related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17-related ID and ASD.