Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Orthopedics

Background:

• Clubfoot is a common birth defect affecting muscle development, with underdeveloped calf muscles observed even after treatment.
• Mutations in genes encoding muscle contractile proteins are known to cause congenital contractures, including clubfoot, in distal arthrogryposis syndromes.

Purpose of the Study:

• To investigate the association between genetic variations in myofiber contractility genes and the etiology of isolated clubfoot.
• To identify specific single nucleotide polymorphisms (SNPs) and gene interactions contributing to clubfoot development.

Main Methods:

• Genomic DNA was analyzed from non-Hispanic White (NHW) and Hispanic families with clubfoot.
• 15 genes encoding myofiber contractility proteins were interrogated for associations with clubfoot using SNP analysis.
• Statistical tests including Hardy-Weinberg equilibrium, relative risk, and likelihood ratio tests were employed for validation.

Main Results:

• Positive associations (P < 0.05) were found with SNPs in 12 out of 15 investigated genes in the NHW discovery cohort.
• TNNC2 gene SNPs showed deviation from Hardy-Weinberg equilibrium and evidence for maternal and inherited genotypic effects.
• Multiple SNPs in the TPM1 gene demonstrated significant associations across discovery, family-based, and case-control validation datasets.
• Gene interactions were identified among muscle contraction genes, often involving regulatory SNPs.

Conclusions:

• Variations in genes encoding skeletal myofiber contractile proteins are suggested as potential contributors to the etiology of clubfoot.
• Specific SNPs in TNNC2 and TPM1, along with gene interactions, may play a role in clubfoot development.
• Further research into these genetic factors could elucidate the underlying mechanisms of clubfoot.