Amelogenesis imperfecta

Gene: TP63

Green List (high evidence)

Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). The association is supported by a knockout mouse model, showing absence of hair follicles, teeth and mammary glands (PMID: 10227293). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.

Created: 7 Nov 2025, 4:04 p.m. | Last Modified: 7 Nov 2025, 4:07 p.m.

Panel Version: 4.16

PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Seq method: WES in probands and Sanger in family members.
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).

Created: 7 Nov 2025, 3:53 p.m. | Last Modified: 7 Nov 2025, 3:54 p.m.

Panel Version: 4.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292

Publications

• 10227293
• 22065540
• 31050217
• 33126320

Green List (high evidence)

https://doi.org/10.1016/j.adoms.2022.100253

This review paper details the main features of TP63 associated diseases
Compared to healthy individuals, patients with ectodermal dysplasia have fewer teeth. Teeth can also be malformed (conical shape) and have poor enamel formation, causing subsequent tooth decay.

It also has an oral radiograph which shows the oral phenotype - the teeth have only a thin layer of enamel if it is present at all.

Created: 17 Jul 2025, 1:57 p.m. | Last Modified: 17 Jul 2025, 1:57 p.m.

Panel Version: 4.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ectodermal dysplasia; split hand/foot malformation; orofacial defect; dry skin; wiry hair; fewer teeth; malformed teeth; amelogenesis imperfecta; dystrophic nails; reduced sweat glands; mammary gland and nipple hypoplasia; lacrimal duct defects

Publications

• PMID:not listed

PMID:22065540 report a mother and son with split hand-split foot. The son was affected with amelogenesis imperfecta. Mutation analysis showed a heterozygous c.588-2A > C mutation in TP63 in the mother and her son. This is the first report of amelogenesis imperfecta associated with a TP63 mutation.

Created: 12 Jun 2017, 9:13 a.m.