Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases, 2024, Misra et al.

Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases
Misra, Kaalindi; Ślęczkowska, Milena; Santoro, Silvia; Gerrits, Monique M.; Mascia, Elisabetta; Marchi, Margherita; Salvi, Erika; Smeets, Hubert J. M.; Hoeijmakers, Janneke G. J.; Martinelli Boneschi, Filippo Giovanni; Filippi, Massimo; Lauria Pinter, Giuseppe; Faber, Catharina G.; Esposito, Federica

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited.

After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance.

Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the “Nicotinic acetylcholine receptor signaling pathway”.

Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

Top 10 genes in patients —

SCN9A
TRPA1
ATP7B
SCN10A
COL7A1
WFS1
NAGLU
SCN11A
TRPM8
TRPV1