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<p>Mutations in the <i>choline acetyltransferase</i> (<i>CHAT</i>) gene cause congenital myasthenic syndrome (CMS). Episodic apnea is frequently observed in patients with CMS due to <i>CHAT</i> mutations (CMS-CHAT), and muscle hypotonia at birth or in early infancy is also common. We report two siblings with compound heterozygous mutations in the <i>CHAT</i> gene: c.1231G &gt; A (missense) and c.752 + 2&#xa0;T &gt; C (splice site). To confirm the splice site mutation induces a splicing variant, we performed a minigene assay and demonstrated that the splice site mutation, c.752 + 2&#xa0;T &gt; C, results in complete exon skipping. AlphaFold2 analysis predicted that the skipped exon constitutes an α helix, a highly conserved core structural element of ChAT. These structural alterations in ChAT may underlie the clinical phenotype associated with these mutations.</p>

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Compound heterozygous CHAT gene mutations, a missense and a splice site variant, in two siblings with congenital myasthenic syndrome

  • 期刊论文

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  • 发表日期：

    2026年2月16日

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  • Shin Kikuchi,
  • Nobuhiro Wada,
  • Tasuku Mariya,
  • Aki Ishikawa,
  • Minako Kihara,
  • Sawako Furukawa,
  • Hidekazu Kato,
  • Yosuke Nishio,
  • Tomoo Ogi,
  • Yuki Ohsaki,
  • Nobutada Tachi

摘要

Mutations in the choline acetyltransferase (CHAT) gene cause congenital myasthenic syndrome (CMS). Episodic apnea is frequently observed in patients with CMS due to CHAT mutations (CMS-CHAT), and muscle hypotonia at birth or in early infancy is also common. We report two siblings with compound heterozygous mutations in the CHAT gene: c.1231G > A (missense) and c.752 + 2 T > C (splice site). To confirm the splice site mutation induces a splicing variant, we performed a minigene assay and demonstrated that the splice site mutation, c.752 + 2 T > C, results in complete exon skipping. AlphaFold2 analysis predicted that the skipped exon constitutes an α helix, a highly conserved core structural element of ChAT. These structural alterations in ChAT may underlie the clinical phenotype associated with these mutations.