Uncovering phenotypic expansion in AXIN2-related disorders through precision animal modeling
Aceves-Ewing, Nathalie M Lanza, Denise G Marcogliese, Paul C Lu, Di Hsu, Chih-Wei Hashimoto, Hirokazu Gonzalez, Matthew Christiansen, Audrey E Rasmussen, Tara L Ho, Alex J
Aceves-Ewing, Nathalie M
Lanza, Denise G
Marcogliese, Paul C
Lu, Di
Hsu, Chih-Wei
Hashimoto, Hirokazu
Gonzalez, Matthew
Christiansen, Audrey E
Rasmussen, Tara L
Ho, Alex J
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.
MIDER Authors
Affiliations
Date
2026-07-09
Type
Article
Collections
Citation
Aceves-Ewing NM, Lanza DG, Marcogliese PC, Lu D, Hsu CW, Hashimoto H, Gonzalez M, Christiansen AE, Rasmussen TL, Ho AJ, Gaspero A, Sha C, Dickinson ME, Yuan B, Shayota BJ, Pachter S, Hu X, Day-Salvatore DL, Mackay L, Kanca O, Wangler MF, Potocki L, Rosenfeld JA, Lewis RA, Chao HT, Lee B, Blieden L, Wasserman BN, Bax DA, Ragge NK, Lee S; Undiagnosed Diseases Network; Baylor College of Medicine Center for Precision Medicine Models; Yamamoto S, Bellen HJ, Burrage LC, Heaney JD. Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling. Genet Med. 2026 Jul 9:102648. doi: 10.1016/j.gim.2026.102648. Epub ahead of print.