New missense variants in RELT causing hypomineralised amelogenesis imperfecta

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

Research output: Contribution to journalArticlepeer-review


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 computerized 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalClinical Genetics
Early online date12 Feb 2020
Publication statusE-pub ahead of print - 12 Feb 2020


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