# 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.

## Key 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.