Amelogenesis imperfecta

Gene: LAMC2

Comment on list classification: Keeping the rating as amber. 1 reported case (PMID: 37228816) but with no phenotype for the mother who also carries the variant in LAMC2. Supportive mouse model in (PMID:26956061).

Created: 17 Jun 2025, 10:46 p.m. | Last Modified: 17 Jun 2025, 10:46 p.m.

Panel Version: 4.5

Comment on mode of inheritance: Updating the mode of inheritance to monoallelic since in the only reported case the proband was heterozygous for a variant in LAMC2.

Created: 17 Jun 2025, 10:41 p.m. | Last Modified: 17 Jun 2025, 10:41 p.m.

Panel Version: 4.3

I don't know

PMID: 37228816 Bloch-Zupan et al. 2023 report one family with LAMC2 mutations as part of a larger panel of sequenced individuals. They report a single child as being affected with a hypoplastic/hypomature AI phenotype. The primary dentition is described as showing thin white opaque enamel.

They identified a heterozygous LAMC2 variant NM_005562.3: c.493C>T; p.(Arg165Cys) with an allele frequency of 0.2% in GnomAD, predicted deleterious by SIFT (v4.0.3) and PolyPhen-2 and located in the Laminin EGF domain. The authors highlight that the enamel formation defects in mice (Wazen et al., 2016) and the patient’s phenotype are similar to the one another. The allele is inherited from her mother but the mother's phenotype was not available.

Notably the patient was sequenced using whole exome sequencing using the following parameters: Non-pathogenic variants were filtered out via: 1) variants represented with an allele frequency of more than 1% in public variation databases including the 1,000 Genomes, the GnomAD database or their internal exome database, variants in 5′ or 3′ UTR, variants with intronic locations and no prediction of local splice effect, and synonymous variants without pathogenic prediction of local splice effect.

Annotations of structural variations (SV) were performed by AnnotSV (Geoffroy et al., 2018). No other findings are presented for the individual.

In conclusion, I do not believe this is strong enough evidence to conclude that this LAMC2 mutation is the cause of disease in this family due to the lack of phenotype information for the mother or any modelling of the effects of the variant, but it is suggestive and additional publications with further families might provide more solid evidence to elevate this gene to green. I would currently consider this gene to be rated amber.

Created: 22 May 2025, 2:45 p.m. | Last Modified: 22 May 2025, 2:45 p.m.

Panel Version: 4.1

Whilst biallelic mutations in LAMC2 are reported to cause Junctional Epidermolysis Bullosa (JEB) which may manifest amelogenesis imperfecta as part of its phenotype (when LAMA3 or LAMB3 genes are mutated), there are no obvious reports of patients with biallelic LAMC2 variants with enamel defects. Neither are heterozygous LAMC2 mutation carriers listed as having enamel defects. However, mutations in LAMA3 and LAMB3 have been shown to cause AI in some heterozygous carriers, so as LAMC2 variants are less frequently identified in cases of JEB, it may be that such carriers exist with AI but have not yet been identified. Reports on patients with LAMC2 variants lack detail as to whether there is enamel pathology or not, however it is a candidate gene due to it being part of a heterotrimeric protein with LAMA3 and LAMB3. Because of this, it is included in the Leeds AI Diagnostic Gene panel, contact Ruth Charlton, Leeds Teaching Hospitals.

Created: 18 Sep 2017, 3:36 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epidermolysis bullosa, junctional, Herlitz type, Epidermolysis bullosa, junctional, non Herlitz type

Publications

• PMID:26956061

Mode of pathogenicity
Other

Comment on mode of inheritance: Updated MOI to 'BOTH monoallelic and biallelic' after clinical agreement from Arianna Tucci to capture potential biallelic JEB patients with enamel defects, and heterozygous carriers with amelogenesis imperfecta.

Created: 31 Oct 2017, 2:25 p.m.

Comment on list classification: After internal discussion, updated the rating from Red to Amber. Although the evidence for being on the Leeds diagnostic panel is indirect (part of a complex with LAMA3 and LAMB3), LAMC2 is listed in the 'prior genetic testing' inclusion list.

Created: 19 Oct 2017, 7:51 a.m.

Comment on list classification: Kept rating as Red as there are currently insufficient cases of LAMC2 heterozygous carriers or LAMC2 biallelic JEB patients with enamel defects (see comment from expert Claire Smith). Added 'watchlist' tag to stay informed about additional cases.

Created: 18 Oct 2017, 11:35 a.m.

UKGTN gene dosier notes say that LAMC2 is not yet identified as a cause of AI in isolation, but is an excellent candidate.

Created: 8 Jun 2017, 10:09 a.m.

Comment on mode of inheritance: Monoallelic MOI taken from UKGTN gene dosier for 21-gene Amelogenesis imperfecta panel.

Created: 8 Jun 2017, 10:08 a.m.