A novel splice site variant in <i>DEGS1</i> leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.

ABSTRACT:

Purpose

Pathogenic DEGS1 variants have been reported in individuals with autosomal recessive hypomyelinating leukodystrophy 18 (HLD18; MIM# 618404). We sought to resolve a 5' +4/+5 splice site variant of uncertain significance found in three individuals with HLD features.

Methods

We used next-generation DNA and transcriptome sequencing, cell-based splicing assays, and tandem mass spectrometry to detect and characterize the splice site variant. We then performed RNA structure probing and conventional antisense oligonucleotide screening to investigate molecular mechanisms for potential therapeutic intervention.

Results

A homozygous, DEGS1 5' splice site variant, c.825+4_825+5delAGinsTT (NM_003676.4) was identified in all three participants. Although the ge

SUBMITTER: Beale HC 

PROVIDER: S-EPMC12036379 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature