Amelogenesis imperfecta

Gene: CLDN16

Green List (high evidence)

Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The dental defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.

Created: 7 Nov 2025, 12:29 p.m. | Last Modified: 7 Nov 2025, 12:29 p.m.

Panel Version: 4.9

PMID: 26426912 Bardet et al., 2016
Report of CLDN16 mutations which result in amelogenesis imperfecta (AI) in 5 unrelated patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Patient 1 was compound heterozygous for p.Ala139Val and p.Lys183Asnfs*2 - non-consanguineous family from Congo. Patients 2-4 from consanguineous families (Morocco, Portugal, Senegal) were all homozygous for a CLDN16 missense variant each (p.Ala139Val, p.Gly162Val, p.Gly239Arg). Patient 5 from a Brazilian consanguineous family was homozygous for CLDN16 deletion of exons 2-5: c.325?_c918*+? (E2_E5del).
All the patients presented enamel defects, including enamel hypoplasia and hypomaturation. Several permanent teeth had failed to erupt in patients 1 and 2. Patients were diagnosed with amelogenesis imperfecta between age 6 and age 45.
Study also included a mouse Cldn16−/− model of FHHNC showing that CLDN16 deficiency led to altered secretory ameloblast structure, lowering of extracellular pH, and abnormal enamel matrix protein processing (functional evidence).

PMID: 32710267 Radonsky et al., 2020
Reports case of a 5yo boy with early clinical renal manifestations (onset at 1 yr) - confirmed nephrocalcinosis. He also presented with dental hypoplasia, growth delay, vomiting, polyuria, polydipsia, and amelogenesis imperfecta with discoloured teeth. Laboratory tests revealed hyperparathyroidism, hypomagnesemia, severe hypercalciuria, and hypermagnesuria. A dental X-ray at 14yo showed mild hypomature amelogenesis imperfecta. Homozygous for a CLDN16 deletion of exons 2-5: c.325_c918*? (E2_E5del). Seq method: WES.

This gene is associated with AR Hypomagnesemia 3, renal, 248250 (OMIM accessed 7th Nov 2025).

Created: 7 Nov 2025, 12:11 p.m. | Last Modified: 7 Nov 2025, 12:11 p.m.

Panel Version: 4.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624; amelogenesis imperfecta, MONDO:0019507

Publications

• 26426912
• 32710267

Green List (high evidence)

In addition to the cases described previously by PMID:26426912, this is an additional report of homozygous deletion of exons 2-5: CLDN16 E2_E5 homozygous deletion c.325_c918*? (E2_E5del) in a 5-year-old boy.

This was identified through whole exome sequencing and was confirmed by MLPA. Patient had hyperparathyroidism, episodes of vomiting, polyuria, and polydipsia that began in the first year of life and normal glycemia, as well as recurrent sterile leukocyturia, short stature (3rd percentile) and permanent teeth that were discolored, indicating amelogenesis imperfecta. Unenhanced helical computed tomography confirmed the presence of a severe form of nephrocalcinosis. Relatives did not have these phenotypes.

I recommend this gene be added to the green list.

Created: 14 Jul 2025, 10:49 a.m. | Last Modified: 14 Jul 2025, 10:49 a.m.

Panel Version: 4.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
amelogenesis imperfecta; hyperparathyroidism; short stature; nephrocalcinosis; polyuria; polydipsia

Publications

• 32710267

PMID:26426912 found homozygous or compound heterozygous CLDN16 mutations in 5 unrelated patients with FHHNC and amelogenesis imperfecta (AI)- all mutations are predicted to be pathogenic, and at least one has previously-confirmed pathogenicity. They also present a mouse model where CLDN16 deficiency leads to enamel phenotype resembling human AI.

Created: 12 Jun 2017, 9:11 a.m.