Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling.

Area of Science:

• Genetics and Developmental Biology
• Molecular Biology
• Human Disease Genetics

Background:

• Heterozygous pathogenic variants in AXIN2 gene are linked to oligodontia-colorectal cancer syndrome (ODCRCS).
• ODCRCS is characterized by missing teeth, colorectal cancer, and sometimes sparse hair/eyebrows.

Purpose of the Study:

• To identify and characterize novel AXIN2 variants and their associated phenotypes.
• To investigate the functional impact of these variants on AXIN2 protein and WNT signaling.

Main Methods:

• Identified four individuals with de novo heterozygous AXIN2 variants.
• Utilized structural modeling to predict variant effects on tankyrase binding.
• Employed prime editing in mouse embryos and Drosophila models to assess in vivo and cell-specific functions.

Main Results:

• Identified two de novo AXIN2 variants (c.196G>A, p.(Glu66Lys) and c.199G>A, p.(Gly67Arg)) expanding the disorder phenotype.
• Affected individuals presented with global developmental delay, microcephaly, and limb, ophthalmologic, and renal abnormalities in addition to ODCRCS features.
• Mouse models showed perinatal lethality with skeletal abnormalities, while Drosophila models exhibited context-dependent gain- and loss-of-function activities.

Conclusions:

• Specific AXIN2 variants in the tankyrase-binding domain are pathogenic, causing a broader spectrum of congenital anomalies.
• Variant pathogenicity is linked to disrupted tankyrase binding, affecting AXIN2 stability and WNT signaling.
• The study highlights context-dependent functional effects of AXIN2 variants and proposes modeling strategies for variant of uncertain significance resolution.