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<p>Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in <i>EPRS1</i>, but exonic deletions have not been reported. We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination. Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of <i>EPRS1</i> (c.3430&#xa0;C &gt; G; p.Leu1144Val, NM_004446.3), without second variant. Whole-genome sequencing revealed a heterozygous 220-bp deletion spanning exon 15 (c.1743-30_1932del), and segregation analysis confirmed compound heterozygosity. RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele. These findings support loss-of-function for the deletion and classify c.3430&#xa0;C &gt; G as likely pathogenic under ACMG/AMP criteria (PM1, PM2, PM3, PP3). This case represents the first exonic deletion reported in <i>EPRS1</i>. The relatively mild, adult-onset phenotype broadens both mutational and clinical spectra of HLD15 and highlights the importance of structural-variant analysis when only a single candidate variant is detected in recessive leukodystrophy.</p>

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Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15

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  • 发表日期：

    2026年2月21日

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  • Akihiko Mitsutake,
  • Takashi Matsukawa,
  • Kenta Orimo,
  • Kunihiro Ueda,
  • Tomonari Seki,
  • Yasushi Shiio,
  • Jun Mitsui,
  • Hiroyuki Ishiura,
  • Harushi Mori,
  • Shoji Tsuji,
  • Tatsushi Toda

摘要

Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in EPRS1, but exonic deletions have not been reported. We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination. Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of EPRS1 (c.3430 C > G; p.Leu1144Val, NM_004446.3), without second variant. Whole-genome sequencing revealed a heterozygous 220-bp deletion spanning exon 15 (c.1743-30_1932del), and segregation analysis confirmed compound heterozygosity. RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele. These findings support loss-of-function for the deletion and classify c.3430 C > G as likely pathogenic under ACMG/AMP criteria (PM1, PM2, PM3, PP3). This case represents the first exonic deletion reported in EPRS1. The relatively mild, adult-onset phenotype broadens both mutational and clinical spectra of HLD15 and highlights the importance of structural-variant analysis when only a single candidate variant is detected in recessive leukodystrophy.