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

Variants in the tankyrase-binding domain of AXIN2 with gain-of-function or dominant-negative effect on Wnt signaling

Heterozygous pathogenic AXIN2 variants cause oligodontia-colorectal cancer syndrome. The authors identify five individuals with de novo heterozygous variants clustered in the tankyrase-binding domain (p.Glu66Lys, p.Glu66Gly, p.Gly67Arg), associating ectodermal dysplasia, global developmental delay, microcephaly and limb, ophthalmologic and genitourinary anomalies. Base-editing modeling in mouse embryos (perinatal lethality, cleft palate, skeletal defects) and Drosophila suggests gain-of-function or dominant-negative effects on Wnt signaling. These tankyrase-domain variants expand the AXIN2 phenotypic spectrum.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The precision animal-modeling approach (mouse N1, Drosophila) provides convincing functional proof of a phenotypic expansion tied to a specific AXIN2 domain. The non-loss-of-function mechanism is clinically important for distinguishing these variants from classic ODCRCS. The N1 strategy could help resolve other heterozygous variants of uncertain significance.

Analysis by Dr Thibaut Benquey