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New missense variants in RELT causing hypomineralised amelogenesis imperfecta

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,...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216828/
https://www.ncbi.nlm.nih.gov/pubmed/32052416
http://dx.doi.org/10.1111/cge.13721
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author 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.
author_facet 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.
author_sort Nikolopoulos, Georgios
collection PubMed
description 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.
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spelling pubmed-72168282020-05-13 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. Clin Genet Original Articles 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. Blackwell Publishing Ltd 2020-02-21 2020-05 /pmc/articles/PMC7216828/ /pubmed/32052416 http://dx.doi.org/10.1111/cge.13721 Text en © 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
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.
New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title_full New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title_fullStr New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title_full_unstemmed New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title_short New missense variants in RELT causing hypomineralised amelogenesis imperfecta
title_sort new missense variants in relt causing hypomineralised amelogenesis imperfecta
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216828/
https://www.ncbi.nlm.nih.gov/pubmed/32052416
http://dx.doi.org/10.1111/cge.13721
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