RELT – Amelogenesis Imperfecta

Recent multi‐family studies have strongly associated biallelic RELT variants with amelogenesis imperfecta, a condition characterized by hypomineralized dental enamel. In two independent studies, affected individuals from four (PMID:32052416) and seven families (PMID:37670079) respectively carried homozygous mutations in RELT. These studies consistently demonstrate an autosomal recessive inheritance pattern where affected probands harbor pathogenic missense alterations that disrupt enamel formation.

The genetic evidence is underpinned by clear segregation analyses, with affected family members sharing a common founder haplotype for the c.164C>T (p.Thr55Ile) variant, solidifying its role in causing the enamel phenotype (PMID:32052416). Additional independent case series further support the deleterious impact of RELT missense mutations and suggest that this variant recurs in distinct populations.

Functional assessments using computerized tomography and scanning electron microscopy provided key insights into the enamel microstructure, demonstrating that RELT dysfunction disrupts ameloblast coordination and enamel matrix organization (PMID:32052416). Furthermore, biochemical assays that explored protein interactions and phosphorylation events lend additional credence to the role of RELT in enamel development (PMID:16389068).

Some reports have noted cases of digenic inheritance involving RELT alongside other enamel-related genes; however, these instances do not detract from the clear, robust evidence linking biallelic RELT variants to a non-syndromic amelogenesis imperfecta phenotype. The genetic and functional data together provide a coherent narrative that builds an essential framework for diagnostic decision‑making in dental genetics.

Overall, the recurrent identification of the c.164C>T (p.Thr55Ile) variant and its demonstrated impact on enamel formation reinforce the clinical significance of RELT screening in patients with amelogenesis imperfecta. This integrated evidence supports the use of RELT variant analysis in clinical and commercial genetic testing settings.

Key take‑home sentence: Biallelic pathogenic variants in RELT are robustly associated with autosomal recessive amelogenesis imperfecta, making it a critical gene to screen in diagnostic evaluations.

References

• Clinical genetics • 2020 • New missense variants in RELT causing hypomineralised amelogenesis imperfecta PMID:32052416
• European journal of human genetics • 2023 • Oro-dental phenotyping and report of three families with RELT-associated amelogenesis imperfecta PMID:37670079
• Biochemical and biophysical research communications • 2006 • Identification of RELT homologues that associate with RELT and are phosphorylated by OSR1 PMID:16389068

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