AXIN1 mutations in nonsyndromic craniosynostosis

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Medicine

Background:

• Craniosynostosis (CS) is the most common cranial birth defect, affecting 1 in 2000 live births.
• While genetic causes for syndromic CS are known, the etiology of most nonsyndromic CS cases remains elusive.

Purpose of the Study:

• To investigate the genetic underpinnings of nonsyndromic craniosynostosis.
• To identify novel genetic variants associated with this condition.

Main Methods:

• Exome or RNA sequencing data from 876 children with nonsyndromic CS were analyzed.
• GeneMatcher and the Gabriella Miller Kids First genome sequencing project were used to find additional patients with AXIN1 mutations.

Main Results:

• Eleven patients with nonsyndromic CS and rare, damaging mutations in AXIN1 were identified.
• AXIN1 mutations were significantly enriched in nonsyndromic CS patients compared to controls (p < 2.3 × 10-6).
• Three of six mutations in trios were de novo, while three were inherited from unaffected parents.

Conclusions:

• This study establishes the first phenotype associated with AXIN1 mutations, implicating it in approximately 1% of nonsyndromic CS cases.
• The findings reinforce the role of Wnt signaling in cranial suture development.
• These results have implications for genetic testing strategies in families affected by CS.