New missense variants in RELT causing hypomineralised amelogenesis imperfecta

Area of Science:

• Genetics
• Developmental Biology
• Oral Health

Background:

• Amelogenesis imperfecta (AI) is a group of genetic disorders affecting tooth enamel formation.
• Mutations in numerous genes are known to cause AI, which can be syndromic or non-syndromic.
• Recent studies linked recessive AI to variants in RELT, a gene encoding a tumor necrosis factor superfamily receptor, sometimes associated with syndromic features.

Purpose of the Study:

• To identify novel mutations in the RELT gene causing autosomal recessive hypomineralized AI.
• To investigate the phenotypic presentation of individuals with new RELT mutations.
• To analyze the effects of RELT mutations on tooth microstructure and enamel formation.

Main Methods:

• Genetic analysis of four families with autosomal recessive hypomineralized AI.
• Whole-exome sequencing to identify causative mutations.
• Computerized tomography and scanning electron microscopy to examine tooth microstructure.
• Microsatellite genotyping to investigate founder effects.

Main Results:

• Four families presented with previously unreported homozygous mutations in the RELT gene (c.164C>T, p.(T55I) and c.1264C>T, p.(R422W)).
• Affected individuals showed hypomineralized AI but lacked other syndromic symptoms like small stature or severe infections.
• Analysis revealed potential roles for RELT in ameloblast coordination and enamel matrix interaction.
• A founder mutation (T55I) was identified in the UK Pakistani population.

Conclusions:

• This study expands the spectrum of RELT pathogenic variants associated with AI.
• New RELT mutations cause autosomal recessive hypomineralized AI without syndromic features in these families.
• RELT plays a role in amelogenesis, and a founder mutation exists in the UK Pakistani population.