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<p>Pontocerebellar hypoplasia type 2 (PCH2) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in tRNA splicing endonuclease (TSEN) subunit genes. Variants in <i>TSEN54</i> are most common, with very few cases of <i>TSEN2</i>-related PCH2B reported to date. Here, we report a 7-year-old girl with typical PCH2 features, including progressive microcephaly, epilepsy, developmental delay, cerebellar atrophy, and dystonia. Exome sequencing revealed compound heterozygous <i>TSEN2</i> variants, a known missense variant NM_025265.4:c.926A&gt;G p.(Tyr309Cys) and a novel nonsense variant c.1048C&gt;T p.(Arg350*). Structural modeling suggested that p.(Tyr309Cys) moderately destabilizes the TSEN2–TSEN54 interface, while p.(Arg350*) truncates the catalytic domain. Despite a minor predicted impact on structure, p.(Tyr309Cys) was associated with severe clinical symptoms in both homozygous and compound heterozygous states. This study expands the <i>TSEN2</i> mutation spectrum and highlights the utility of integrating structural modeling with clinical data to refine genotype–phenotype correlations in PCH2B.</p>

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Biallelic TSEN2 variants causing pontocerebellar hypoplasia type 2

  • 期刊论文

  • 发表日期：

    2025年8月27日

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  • Yukina Hayashi,
  • Keisuke Hamada,
  • Kavitha Rethanavelu,
  • Naomi Tsuchida,
  • Yuri Uchiyama,
  • Eriko Koshimizu,
  • Satoko Miyatake,
  • Takeshi Mizuguchi,
  • Kazuhiro Ogata,
  • Atsushi Fujita,
  • Naomichi Matsumoto

摘要

Pontocerebellar hypoplasia type 2 (PCH2) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in tRNA splicing endonuclease (TSEN) subunit genes. Variants in TSEN54 are most common, with very few cases of TSEN2-related PCH2B reported to date. Here, we report a 7-year-old girl with typical PCH2 features, including progressive microcephaly, epilepsy, developmental delay, cerebellar atrophy, and dystonia. Exome sequencing revealed compound heterozygous TSEN2 variants, a known missense variant NM_025265.4:c.926A>G p.(Tyr309Cys) and a novel nonsense variant c.1048C>T p.(Arg350*). Structural modeling suggested that p.(Tyr309Cys) moderately destabilizes the TSEN2–TSEN54 interface, while p.(Arg350*) truncates the catalytic domain. Despite a minor predicted impact on structure, p.(Tyr309Cys) was associated with severe clinical symptoms in both homozygous and compound heterozygous states. This study expands the TSEN2 mutation spectrum and highlights the utility of integrating structural modeling with clinical data to refine genotype–phenotype correlations in PCH2B.