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<p>Pathogenic SNF2 related chromatin remodeling ATPase 1 (<i>SMARCA1</i>) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel <i>SMARCA1</i> variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous <i>SMARCA1</i> variant (NM_003069.5:c.1795 C &gt; T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G &gt; T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between <i>SMARCA1</i> and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing <i>SMARCA1</i> function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.</p>

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Hemizygous SMARCA1 variants cause X-linked intellectual disability

  • 期刊论文

  • 发表日期：

    2025年5月2日

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  • Naoto Nishimura,
  • Takeshi Mizuguchi,
  • Keisuke Hamada,
  • Kotaro Yuge,
  • Masamune Sakamoto,
  • Naomi Tsuchida,
  • Yuri Uchiyama,
  • Atsushi Fujita,
  • Eriko Koshimizu,
  • Kazuharu Misawa,
  • Satoko Miyatake,
  • Yoriko Watanabe,
  • Hitoshi Osaka,
  • Koh-Ichiro Yoshiura,
  • Kazuhiro Ogata,
  • Naomichi Matsumoto

摘要

Pathogenic SNF2 related chromatin remodeling ATPase 1 (SMARCA1) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel SMARCA1 variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous SMARCA1 variant (NM_003069.5:c.1795 C > T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G > T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between SMARCA1 and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing SMARCA1 function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.