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Updated: May 20, 2026

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
ALX4 gain-of-function mutations in nonsyndromic craniosynostosis
Garima Yagnik1, Apar Ghuman, Sundon Kim
1Section of Genetics, Department of Pediatrics, University of California-Davis, Sacramento, CA 95817, USA.
Abstract:
Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Nonsyndromic craniosynostosis (NSC) accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved nonsyndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC.
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