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Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East
We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp i...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106946/ https://www.ncbi.nlm.nih.gov/pubmed/30174688 http://dx.doi.org/10.1155/2018/1284568 |
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author | Abu-Duhier, Faisel Pooranachandran, Vivetha McDonagh, Andrew J. G. Messenger, Andrew G. Cooper-Knock, Johnathan Bakri, Youssef Heath, Paul R. Tazi-Ahnini, Rachid |
author_facet | Abu-Duhier, Faisel Pooranachandran, Vivetha McDonagh, Andrew J. G. Messenger, Andrew G. Cooper-Knock, Johnathan Bakri, Youssef Heath, Paul R. Tazi-Ahnini, Rachid |
author_sort | Abu-Duhier, Faisel |
collection | PubMed |
description | We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp in the SLC39A4 gene which encodes a zinc transporter; disease is thought to result from zinc deficiency. Similar mutations have been reported previously; however, the variable severity within cases carrying the p.Gly512Trp variant and in AE overall led us to hypothesise that additional genetic modifiers may be contributing to the disease phenotype. Therefore whole genome sequencing was carried out in five family members, for whom material was available to search for additional modifiers of AE; this included one individual with clinically diagnosed AE. We confirmed that the p.Gly512Trp change in SLC39A4 was the only candidate homozygous change which was sufficiently rare (ExAC allele frequency 1.178e-05) and predicted deleterious (CADD score 35) to be attributable as a fully penetrant cause of AE. To identify other genes which may carry relevant genetic variation, we reviewed the relevant literature and databases including Gene Ontology Consortium, GeneMANIA, GeneCards, and MalaCards to identify zinc transporter genes and possible interacting partners. The affected individual carried variants in RECQL4 and GPAA1 genes with ExAC allele frequency <0.01 and CADD score >10. p.Gly512Trp is highly likely to be the pathogenic variant in this family. This variant was previously detected in a Tunisian proband with perfect genotype-phenotype segregation suggestive of pathogenicity. Further research is required in this area due to small sample size, but attention should be given to RECQL4 and GPAA1 to understand their role in the skin disease. |
format | Online Article Text |
id | pubmed-6106946 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-61069462018-09-02 Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East Abu-Duhier, Faisel Pooranachandran, Vivetha McDonagh, Andrew J. G. Messenger, Andrew G. Cooper-Knock, Johnathan Bakri, Youssef Heath, Paul R. Tazi-Ahnini, Rachid Dermatol Res Pract Research Article We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp in the SLC39A4 gene which encodes a zinc transporter; disease is thought to result from zinc deficiency. Similar mutations have been reported previously; however, the variable severity within cases carrying the p.Gly512Trp variant and in AE overall led us to hypothesise that additional genetic modifiers may be contributing to the disease phenotype. Therefore whole genome sequencing was carried out in five family members, for whom material was available to search for additional modifiers of AE; this included one individual with clinically diagnosed AE. We confirmed that the p.Gly512Trp change in SLC39A4 was the only candidate homozygous change which was sufficiently rare (ExAC allele frequency 1.178e-05) and predicted deleterious (CADD score 35) to be attributable as a fully penetrant cause of AE. To identify other genes which may carry relevant genetic variation, we reviewed the relevant literature and databases including Gene Ontology Consortium, GeneMANIA, GeneCards, and MalaCards to identify zinc transporter genes and possible interacting partners. The affected individual carried variants in RECQL4 and GPAA1 genes with ExAC allele frequency <0.01 and CADD score >10. p.Gly512Trp is highly likely to be the pathogenic variant in this family. This variant was previously detected in a Tunisian proband with perfect genotype-phenotype segregation suggestive of pathogenicity. Further research is required in this area due to small sample size, but attention should be given to RECQL4 and GPAA1 to understand their role in the skin disease. Hindawi 2018-08-07 /pmc/articles/PMC6106946/ /pubmed/30174688 http://dx.doi.org/10.1155/2018/1284568 Text en Copyright © 2018 Faisel Abu-Duhier et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Abu-Duhier, Faisel Pooranachandran, Vivetha McDonagh, Andrew J. G. Messenger, Andrew G. Cooper-Knock, Johnathan Bakri, Youssef Heath, Paul R. Tazi-Ahnini, Rachid Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title | Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title_full | Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title_fullStr | Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title_full_unstemmed | Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title_short | Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East |
title_sort | whole genome sequencing in an acrodermatitis enteropathica family from the middle east |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106946/ https://www.ncbi.nlm.nih.gov/pubmed/30174688 http://dx.doi.org/10.1155/2018/1284568 |
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