New missense variants in RELT causing hypomineralised amelogenesis imperfecta

Nikolopoulos, Georgios; Smith, Claire E.L.; Brookes, Steven J.; El-Asrag, Mohammed E.; Brown, Catriona J.; Patel, Anesha; Murillo, Gina; O'Connell, Mary J.; Inglehearn, Chris F.; Mighell, Alan J.

Abstract

© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd. 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.

Citation

Nikolopoulos, G., Smith, C. E., Brookes, S. J., El-Asrag, M. E., Brown, C. J., Patel, A., Murillo, G., O'Connell, M. J., Inglehearn, C. F., & Mighell, A. J. (2020). New missense variants in RELT causing hypomineralised amelogenesis imperfecta. Clinical Genetics, 97(5), 688-695. https://doi.org/10.1111/cge.13721

• Journal Article Type: Article
• Acceptance Date: Feb 5, 2020
• Online Publication Date: Feb 12, 2020
• Publication Date: 2020-05
• Deposit Date: Jun 30, 2020
• Publicly Available Date: Jul 2, 2020
• Journal: Clinical Genetics
• Print ISSN: 0009-9163
• Electronic ISSN: 1399-0004
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 97
• Issue: 5
• Pages: 688-695
• DOI: https://doi.org/10.1111/cge.13721
• Keywords: Amelogenesis imperfecta, Enamel, RELT, Tumour necrosis factor receptor
• Public URL: https://nottingham-repository.worktribe.com/output/4371199
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1111/cge.13721
• Additional Information: Received: 2020-01-15; Accepted: 2020-02-05; Published: 2020-02-21