Identification of copy number variants contributing to hallux valgus

Abstract

Hallux valgus is a common form of foot deformity, and genetic factors contribute substantially to the pathogenesis of hallux valgus deformity. We conducted a genetic study on the structural variants underlying familial hallux valgus using whole exome sequencing approach. Twenty individuals from five hallux valgus families and two sporadic cases were included in this study. A total of 372 copy number variations were found and passed quality control filtering. Among them, 43 were only present in cases but not in controls or healthy individuals in the database of genomic variants. The genes covered by these copy number variations were enriched in gene sets related to immune signaling pathway, and cytochrome P450 metabolism. The hereditary CNVs demonstrate a dominant inheritance pattern. Two candidate pathogenic CNVs were further validated by quantitative-PCR. This study suggests that hallux valgus is a degenerative joint disease involving the dysregulation of immune and metabolism signaling pathways.

Keywords: copy number variation; cytochrome p450 metabolism; hallux valgus; immune dysregulation; whole exome sequencing.

FIGURE 1

The family pedigree diagrams for all the subjects in the study. S-1 and S-2 are two sporadic cases. Families F1, F3 and F5 were included in our previous study of single nucleotide variants (Jia et al., 2021).The color indicates the severity of the patient’s illness from mild to severe.

FIGURE 2

The pipeline of copy number variation analysis based on whole exome sequencing data.

FIGURE 3

Pathway and protein-protein interaction analyses on the genes covered by 43 case-only CNVs (A) KEGG pathway enrichment analysis on the genes covered by the 43 case-only CNVs. The color of the dots represents the size of the corrected p-value, and the size of the dots represents the number of input genes contained in the corresponding pathway. (B) Protein-protein interaction analysis on the genes covered by 43 case-only CNVs. The nodes represent the proteins, and the lines between the nodes indicate the interactions between the proteins.

FIGURE 4

qPCR validation of two CNVs. (A) Copy number detected by qPCR at chr22: 42522498–42536739 for F1-I-1, F1-II-1, F1-II-2 and F1-I-2. (B) Copy number detected by qPCR at chr6: 29855550–29895036 for F2-I-1, F2-II-1 and F2-I-2. (C) Copy number detected by qPCR at chr6: 29855550–29895036 for F2-I-1, F2-II-1 and F2-II-2.