Phenotypic variability and craniofacial dysmorphology: increased shape variance in a mouse model for cleft lip

Area of Science:

• Developmental biology
• Genetics
• Craniofacial malformations

Background:

• Cleft lip and palate (CL/P) is a complex human birth defect with variable expression.
• A/WySn mice model human CL/P, exhibiting variable expression, incomplete penetrance, and unilateral occurrence on a consistent genetic background.
• The developmental origins of this expression variability remain largely unknown.

Purpose of the Study:

• To investigate the craniofacial shape variation during primary palate formation in A/WySn mouse embryos.
• To understand the developmental basis for variable CL/P expression in a genetically homogeneous mouse model.

Main Methods:

• Utilized three-dimensional geometric morphometrics.
• Employed high-throughput morphometric techniques using three-dimensional computed microtomography of mouse embryos.
• Analyzed craniofacial shape variation during primary palate formation.

Main Results:

• Confirmed reduced size and developmental delay in the midface, particularly the maxillary prominence, of A/WySn embryos.
• Observed significantly increased craniofacial shape variance in A/WySn embryos compared to control strains (C57BL/6J and F1 crosses).
• Hypothesized that increased shape variance, coupled with reduced midfacial growth from the Wnt9b mutation, contributes to variable CL/P expression.

Conclusions:

• Craniofacial shape variance increases during primary palate formation in A/WySn mouse embryos.
• Elevated shape variance may explain the incomplete penetrance and variable expression of CL/P in this genetically homogeneous mouse model.
• Findings provide a foundation for understanding the developmental mechanisms behind variable craniofacial malformations in humans.