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New missense variants in RELT causing hypomineralised amelogenesis imperfecta
Author(s) -
Nikolopoulos Georgios,
Smith Claire E.L.,
Brookes Steven J.,
ElAsrag Mohammed E.,
Brown Catriona J.,
Patel Anesha,
Murillo Gina,
O'Connell Mary J.,
Inglehearn Chris F.,
Mighell Alan J.
Publication year - 2020
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13721
Subject(s) - amelogenesis imperfecta , missense mutation , genetics , biology , haplotype , exon , phenotype , population , mutation , gene , genotype , medicine , enamel paint , dentistry , environmental health
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.