Amelogenesis imperfecta

Gene: LTBP3

As reviewed by Claire Smith, PMID: 29625025 Guo et al., 2018 reports that individuals with heterozygous LTBP3 variants may also present with a dental phenotype. In family TAA376, 2/6 individuals heterozygous for c.2033_2041delinsCTT were noted to have unspecified 'dental anomalies'. This is in contrast with the homozygous family members, diagnosed with a tooth enamel deficiency. Individuals heterozygous for other LTBP3 variants (family TAA909) did not present with enamel deficiency, either.

Due to incomplete penetrance and a lack of a specific amelogenesis imperfecta phenotype, the MOI for this gene should remain BIALLELIC, until more evidence emerges.

Created: 12 Dec 2025, 12:26 p.m. | Last Modified: 12 Dec 2025, 12:26 p.m.

Panel Version: 4.24

Green List (high evidence)

An earlier review by Eleanor Williams highlights this paper, which states that heterozygous (monoallelic) LTBP3 variants can cause amelogenesis imperfecta, along with other pathology, however this is not all variants, nor all people that carry them. The variant in question was c.2033_2041delinsCTT (p.Asn678_Gly681delinsThrCys). See Figure 1

Perhaps the MOI should be altered to both since monoallelic patients here do sometimes have a dental phenotype?

Created: 18 Nov 2025, 3:41 p.m. | Last Modified: 18 Nov 2025, 3:41 p.m.

Panel Version: 4.24

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 29625025

Comment on phenotypes: OMIM phenotype correct as of 22nd Dec 2025

Created: 22 Dec 2025, 3:43 p.m. | Last Modified: 22 Dec 2025, 3:43 p.m.

Panel Version: 4.25

Leaving the mode of inheritance as Biallelic. Cases reporting a dental phenotype have all had biallelic variants.

Monoallelic cases have also been reported with geleophysic dysplasia and acromelic dysplasia phenotypes and therefore the mode of inheritance on the skeletal dysplasia panel covers both mode of inheritance.

Created: 2 Mar 2022, 6:02 p.m. | Last Modified: 2 Mar 2022, 6:03 p.m.

Panel Version: 2.16

Comment when marking as ready: Associated with phenotype in OMIM and as a confirmed G2P for Platyspondyly with amelogenesis imperfecta. At least 7 variants reported in at least 6 cases of Dental anomalies and short stature 601216.

Created: 8 Jan 2018, 12:52 p.m.

Comment on phenotypes: Monoallelic variants reported in Geleophysic dysplasia 3 617809

Created: 8 Jan 2018, 12:52 p.m.

Comment on mode of inheritance: Monoallelic variants associated with Geleophysic dysplasia 3 617809

Created: 8 Jan 2018, 12:44 p.m.

Comment on list classification: Updated rating from Red to Green, awaiting external review. LTBP3 is included in the 'prior genetic testing' inclusion list and features on the UKGTN 21-gene AI panel. Confirmed DD-G2P gene for 'PLATYSPONDYLY WITH AMELOGENESIS IMPERFECTA' and sufficient cases (>3) to support causation + mouse model reported in PMID:25669657.

Created: 19 Oct 2017, 11:11 a.m.

Comment on mode of inheritance: Biallelic mode of inheritance supported by OMIM and DD-G2P.

Created: 19 Oct 2017, 11:09 a.m.

Comment on publications: PMID:28084688 present a mouse model with Ltbp3-/- mice presenting with unique craniofacial malformations and reductions in enamel formation.

Created: 19 Oct 2017, 11:08 a.m.

PMID:25669657 (2015) report 4 families (3 consanguineous) from different ethnicities (Turkey, French caucasian, Brazil, Pakistan) characterized by significant short stature (platyspondyly/brachyolmia) and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. WES resulted in the identification of recessive variants including deletion, nonsense and splice variants in the LTBP3 gene. All variants segregated with the disease phenotype and were absent in EVS and 1000 genomes catalogs. PMID:25669657 also generated Ltbp3-/- mice with enamel defects.

Created: 19 Oct 2017, 11:06 a.m.