Language

English

Publication Date

7-9-2026

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2026.102648

PMID

42429102

Abstract

Purpose: Heterozygous pathogenic variants in AXIN2 (HGNC 904) cause oligodontia-colorectal cancer syndrome (ODCRCS). We identified five individuals with de novo, heterozygous variants (NM_004655.4:c.196G>A p.(Glu66Lys), c.197A>G p.(Glu66Gly), and c.199G>A p.(Gly67Arg)) in AXIN2. Common phenotypes among these individuals included ectodermal dysplasia, global developmental delay, microcephaly, and limb, ophthalmologic, and genitourinary abnormalities.

Methods: Structural modeling was performed to predict the impact of these variants on AXIN2. A prime editing N1 screen of mouse embryos was performed to test whether the p.Glu66Lys variant produces a phenotype. Drosophila models were used to test the effect of this variant on Wnt signaling.

Results: Structural modeling suggests that these variants disrupt AXIN2 binding to tankyrase, which regulates AXIN2 levels through PARsylation. Heterozygous (p.Glu66Lys) mouse embryos were perinatal lethal with soft palate cleft and skeletal abnormalities. Modeling of the p.Glu66Lys variant in the Drosophila wing suggests gain-of-function or dominant negative activity compared to reference AXIN2.

Conclusions: Specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with potential context-dependent effects on AXIN2 function and Wnt signaling. The N1 modeling strategy used to demonstrate variant pathogenicity may be beneficial for resolving other heterozygous variants associated with congenital anomalies.

Keywords

AXIN2, Wnt/β-catenin signaling, ectodermal dysplasia, oligodontia-colorectal cancer, tankyrase-binding domain

Published Open-Access

yes

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