New missense variants in RELT causing hypomineralised amelogenesis imperfecta.

Abstract

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non-syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix. Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT-variant associated AI.

• Authors: Georgios Nikolopoulos, Claire E L Smith, Steven J Brookes, Mohammed E El-Asrag, Catriona J Brown, Anesha Patel, Gina Murillo, Mary J O'Connell, Chris F Inglehearn, Alan J Mighell
• Journal: Clinical genetics (Clin Genet) Vol. 97 Issue 5 Pg. 688-695 (05 2020) ISSN: 1399-0004 [Electronic] Denmark
• PMID: 32052416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Chemical References

• RELT
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha

Topics

• Amelogenesis Imperfecta (diagnostic imaging, genetics, pathology)
• Exons
• Female
• Genetic Predisposition to Disease
• Homozygote
• Humans
• Male
• Mutation, Missense (genetics)
• Pedigree
• Phenotype
• Receptors, Tumor Necrosis Factor (genetics)
• Tooth Demineralization (diagnostic imaging, genetics, pathology)
• Tumor Necrosis Factor-alpha (genetics)