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

TL;DR

A woman with a rare brain disorder had a new genetic mutation and a deletion in the EPRS1 gene, showing how these changes can cause mild symptoms in adults.

Contribution

This is the first report of an exonic deletion in EPRS1, expanding the genetic and clinical understanding of HLD15.

Findings

Compound heterozygosity of a missense variant and an exonic deletion in EPRS1 was identified in a patient with HLD15.

The deletion caused exon skipping and nonsense-mediated decay, supporting a loss-of-function mechanism.

The case shows a mild, adult-onset phenotype, broadening the known clinical spectrum of HLD15.

Abstract

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.

The online version contains supplementary material available at 10.1007/s10048-026-00885-4.

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