Identification and Targeted Correction of a Pathogenic PMP22 Deep Intronic Variant

PMP22 (deep intronic variant, heterozygous)

Deep intronic PMP22 variant → cryptic pseudo-exon activation → 95 bp insertion in mRNA → truncated protein; in vitro correction demonstrated by antisense oligonucleotide (ASO)

Identification of a deep intronic PMP22 variant causing hereditary demyelinating peripheral neuropathy in a patient with a negative exome. The variant activates a 95 bp cryptic pseudo-exon causing a frameshift and truncated protein. The study also demonstrates in vitro functional correction by antisense oligonucleotide (ASO) targeting the activating intronic sequence, opening a direct therapeutic avenue. This case illustrates the theranostic WGS + ASO paradigm for monogenic diseases with splicing components.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Exemplary case of the differential value of WGS over exome in hereditary neuropathies. The ASO correction demonstration confers immediate theranostic value. Consider in any CMT/HNPP patient with negative exome and compatible family history. Reproducible model for other hereditary neuropathies.

deep intronic mechanism (WGS required) +3; ASO correction demonstrated +2; direct diagnostic impact (exome insufficient) +2; IJMS +1