AI Article Synopsis

  • Clubfoot is a common congenital condition characterized by a rigid inward and downward foot position, with its causes remaining largely unclear despite some known genetic factors.
  • Researchers analyzed exome sequence data from 1190 cases of non-syndromic clubfoot along with their family members, focusing on uncovering rare genetic variants associated with the condition across different ethnicities.
  • The study identified rare variants in 29 genes linked to clubfoot cases, including previously unrecognized genes, and revealed that a small percentage of cases had variants associated with known diseases, expanding the understanding of the genetic basis of clubfoot.

Article Abstract

Background: Clubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants in known clubfoot disease genes account for only a small portion of the heritability.

Methods: Exome sequence data were generated from 1190 non-syndromic clubfoot cases and their family members from multiple ethnicities. Ultra-rare variant burden analysis was performed comparing 857 unrelated clubfoot cases with European ancestry with two independent ethnicity-matched control groups (1043 in-house and 56 885 gnomAD controls). Additional variants in prioritised genes were identified in a larger cohort, including probands with non-European ancestry. Segregation analysis was performed in multiplex families when available.

Results: Rare variants in 29 genes were enriched in clubfoot cases, including (a known clubfoot disease gene), , , and . In addition, rare variants in posterior genes () were enriched overall in clubfoot cases. In total, variants in these genes were present in 8.4% (100/1190) of clubfoot cases with both European and non-European ancestry. Among these, 3 are and 22 show variable penetrance, including 4 variants that segregate with clubfoot.

Conclusion: We report as a novel clubfoot disease gene and demonstrate a phenotypic expansion of known disease genes (myopathy gene , Ehlers-Danlos syndrome gene and nail-patella syndrome gene ) to include isolated clubfoot.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228210PMC
http://dx.doi.org/10.1136/jmg-2024-109846DOI Listing

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