Case Report: A novel deep intronic MFSD8 splice-altering variant causes CLN7 disease through pseudoexon inclusion
- 1Department of Functional Genomics, Research Centre for Medical Genetics , ,
Abstract
Pathogenic deep intronic variants are an underrecognized cause of inherited disorders because they are typically missed by exon-focused sequencing and often require functional validation. We describe a patient with classic CLN7 disease caused by a previously unreported deep intronic variant in MFSD8. The patient presented with developmental regression, progressive epilepsy, cerebellar ataxia, and cerebral and cerebellar atrophy. Trio whole-genome sequencing identified a homozygous MFSD8 variant, NM_001371596.2:c.999-556C>G, absent from population databases and previous reports. SpliceAI predicted activation of cryptic splice sites leading to inclusion of a 98-nt pseudoexon. RNA analysis of patient-derived fibroblasts confirmed aberrant pseudoexon inclusion, resulting in a frameshift and premature termination codon, with the aberrant transcript accounting for 84% of total MFSD8 transcripts. A minigene assay independently reproduced the splicing defect, confirming that the variant disrupts normal MFSD8 splicing. This study expands the mutational spectrum of MFSD8 and provides functional evidence supporting the pathogenicity of a novel deep intronic splice-altering variant. Our findings further demonstrate the value of combining whole-genome sequencing with transcript analysis for the molecular diagnosis of unsolved rare neurogenetic disorders.
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BibTeX
@article{akimova2026case,
title = {{Case Report: A novel deep intronic MFSD8 splice-altering variant causes CLN7 disease through pseudoexon inclusion}},
author = {Daria Akimova and Anait Voskanyan and Anna Orlova and Mikhail Skoblov},
journal = {Frontiers in genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1980180},
url = {https://europepmc.org/article/PMC/PMC13727524},
note = {CC BY},
}
RIS
TY - JOUR
TI - Case Report: A novel deep intronic MFSD8 splice-altering variant causes CLN7 disease through pseudoexon inclusion
AU - Daria Akimova
AU - Anait Voskanyan
AU - Anna Orlova
AU - Mikhail Skoblov
PY - 2026
DA - 2026/10/20
JO - Frontiers in genetics
DO - 10.3389/fgene.2026.1980180
UR - https://europepmc.org/article/PMC/PMC13727524
AB - Pathogenic deep intronic variants are an underrecognized cause of inherited disorders because they are typically missed by exon-focused sequencing and often require functional validation. We describe a patient with classic CLN7 disease caused by a previously unreported deep intronic variant in MFSD8. The patient presented with developmental regression, progressive epilepsy, cerebellar ataxia, and cerebral and cerebellar atrophy. Trio whole-genome sequencing identified a homozygous MFSD8 variant, NM_001371596.2:c.999-556C>G, absent from population databases and previous reports. SpliceAI predicted activation of cryptic splice sites leading to inclusion of a 98-nt pseudoexon. RNA analysis of patient-derived fibroblasts confirmed aberrant pseudoexon inclusion, resulting in a frameshift and premature termination codon, with the aberrant transcript accounting for 84% of total MFSD8 transcripts. A minigene assay independently reproduced the splicing defect, confirming that the variant disrupts normal MFSD8 splicing. This study expands the mutational spectrum of MFSD8 and provides functional evidence supporting the pathogenicity of a novel deep intronic splice-altering variant. Our findings further demonstrate the value of combining whole-genome sequencing with transcript analysis for the molecular diagnosis of unsolved rare neurogenetic disorders.
SN - 1664-8021
ER -