Inherited Variants in the COL11A, COL1A, COL5A1, COMP, GSTM1 Genes and the Risk of Carpal Tunnel Syndrome.

Unlabelled: The pathogenesis of most cases of carpal tunnel syndrome is not clearly defined. There are some aspects of the disease that suggest a potential effect of genetic predispositions. Mutations (variants) within the genes encoding various subtypes of collagen synthesis, oligomerisation in the endoplasmic reticulum and inactivation of reactive oxygen species may be involved in the development of carpal tunnel syndrome. The objective of this study was to determine the role of DNA alterations within the COL11A, COL1A, COL5A1, COMP and GSTM1 genes in the pathogenesis of carpal tunnel syndrome based on a Polish population.

Study Design: In the discovery phase, a total of 96 patients with familial aggregation of CTS were genotyped using a Next Generation Sequencing panel in order to find possible mutations within the studied genes. The potential pathogenicity of the detected variants was investigated using the predictions of several in-silico algorithms and the TaqMan technology. In the association phase of the study, a group of 345 CTS patients and 1035 healthy controls were genotyped.

Results: A total of 35 splice-site or exonic non-synonymous variants were detected by NGS. We did not identify any clearly pathogenic or likely pathogenic alternations. The 30 variants were identified as benign or likely benign. Five missense changes were predicted as VUS and selected for association study. The COL5A1 c.1595 C>T (p.Ala532Val) was detected in one out of 345 cases and three out of 1035 controls (P=1, OR=1); this indicates that the variant is a neutral alteration. Four remaining variants - c.2840 C>A, c.5395 G>A, c.1331 C>G, c.1590 C>A - were present in none out of the 345 CTS patients and none out of 1035 controls.

Conclusion: The main finding of this study was that there was no independent association between the variants of five examined genes and carpal tunnel syndrome. Four uncertain variants were identified that seem to be extremely rare in the Polish population.