Genomic analysis of 21 patients with corneal neuralgia after refractive surgery

Refractive surgery, specifically laser-assisted in situ keratomileusis and photorefractive keratectomy, are widely applied procedures to treat myopia, hyperopia, and astigmatism. After surgery, a subgroup of cases suffers from persistent and intractable pain of obscure etiology, thought to be neuropathic. We aimed to investigate the contribution of genomic factors in the pathogenesis of these patients with corneal neuralgia.

We enrolled 21 cases (6 males and 15 females) from 20 unrelated families, who reported persistent pain (>3 months), after refractive surgery (20 laser-assisted in situ keratomileusis and 1 photorefractive keratectomy patients). Whole-exome sequencing and gene-based association test were performed.

Whole-exome sequencing demonstrated low-frequency variants (allele frequency < 0.05) in electrogenisome-related ion channels and cornea-expressed collagens, most frequently in SCN10A (5 cases), SCN9A (4 cases), TRPV1 (4 cases), CACNA1H and CACNA2D2 (5 cases each), COL5A1 (6 cases), COL6A3 (5 cases), and COL4A2 (4 cases). Two variants, p.K655R of SCN9A and p.Q85R of TRPV1, were previously characterized as gain-of-function. Gene-based association test assessing "damaging" missense variants against gnomAD exome database (non-Finnish European or global), identified a gene, SLC9A3R1, with statistically significant effect (odds ratio = 17.09 or 17.04; Bonferroni-corrected P-value < 0.05).

These findings in a small patient cohort did not identify a common gene/variant among most of these cases, as found in other disorders, for example small-fiber neuropathy. Further studies of these candidate genes/variants might enhance understanding of the role of genetic factors in the pathogenesis of corneal neuralgia.