One family, two variants: double carriers of EDARADD and WNT10A variants show the severe end of tooth agenesis

What the report is

Yu-Chen Jeng, Yu-Fen Yen and colleagues, reporting a Taiwanese clinical case series, published “Delayed tooth eruption as an early clinical indicator of genetical tooth agenesis: A family-based study of cases with whole-exome sequencing” in the Journal of Dental Sciences (doi:10.1016/j.jds.2025.07.3476; free full text at PMC13536374). It is a Short Communication, not a cohort study: five members of one family were genotyped and phenotyped. The proband, a girl of 22 months, had erupted only eight primary teeth, one incisor and one molar per quadrant, after no eruption at all at 15 months; her mother had tooth agenesis plus systemic ectodermal features including anhidrosis. Periapical radiographs taken early were inconclusive because the small, poorly mineralized tooth germs of a toddler cannot be counted reliably, which is exactly the gap the authors say whole-exome sequencing can close.

What the segregation shows

Sequencing, with Sanger confirmation, found two heterozygous variants segregating in the family: EDARADD c.328G>T (p.Asp110Tyr) and WNT10A c.637G>A (p.Gly213Ser). The pattern across the five carriers is the paper’s whole argument. The mother and one relative each carry both variants and have the most severe phenotype, multiple missing teeth with hypohidrotic ectodermal features. A relative carrying only the WNT10A variant has hypodontia without significant systemic involvement. The two relatives carrying only the EDARADD variant sit at opposite ends: the proband shows markedly delayed eruption, while the other has a normal dentition with mild hypohidrotic features such as reduced sweating. The authors read this as a genotype-phenotype gradient in which WNT10A drives tooth agenesis, EDARADD (in the EDA signaling pathway) modulates eruption timing and ectodermal signs, and carrying both pushes a carrier toward the severe end. They support the digenic idea at the pathway level by citing prior reports that WNT10A deficiency produces distinct dental phenotypes and that combined EDA-pathway variants can raise the frequency and severity of agenesis.

What it does not show

The digenic claim rests on a five-person segregation pattern, not on functional data. The paper reports no ACMG classification, no in silico pathogenicity predictions, no population-frequency data, and no variant-specific prior literature for either allele, so neither variant’s pathogenicity is formally established here. There is no biochemical or cellular demonstration that the two variants interact. And a single family cannot establish how common digenic inheritance is among people with hypodontia generally. The clinical message, that delayed eruption in a toddler can be the first sign of genetically driven agenesis and that exome sequencing is useful when radiographs are inconclusive, is modest and well supported by the case; the genetic architecture claim is hypothesis-grade.

Why the third dentition record cares

The anti-USAG-1 / TRG-035 program exists because of patients like these: severe congenital partial anodontia is its orphan-drug indication, and the EDA and WNT pathways this family implicates are the same developmental signaling space that USAG-1, a BMP/Wnt antagonist, sits in. This paper does not change the program’s status: no human tooth regeneration result is in it, and it is a diagnostic-genetics report, not a therapy study. What it adds to the record is phenotype granularity. The third dentition field tends to speak of “congenital anodontia” as a block; this family’s gradient, from normal dentition through delayed eruption and isolated hypodontia to severe agenesis with ectodermal disease, mapped onto just two heterozygous variants, is a concrete reminder that the target population is genetically heterogeneous, and that trial endpoints such as eruption timing will need to account for that heterogeneity. The field assessment does not move on this record.

Provenance: grounded in the full text of Jeng et al. (2026), Journal of Dental Sciences 21(3):1965, doi:10.1016/j.jds.2025.07.3476, retrieved via PubMed Central (PMC13536374) on 27 September 2026. See /method/.