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Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome
To comprehensively evaluate a European–American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a mu...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111009/ https://www.ncbi.nlm.nih.gov/pubmed/27900368 http://dx.doi.org/10.1101/mcs.a001255 |
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author | Polfus, Linda M. Boerwinkle, Eric Gibbs, Richard A. Metcalf, Ginger Muzny, Donna Veeraraghavan, Narayanan Grove, Megan Shete, Sanjay Wallace, Stephanie Milewicz, Dianna Hanchard, Neil Lupski, James R. Hashmi, Syed Shahrukh Gupta-Malhotra, Monesha |
author_facet | Polfus, Linda M. Boerwinkle, Eric Gibbs, Richard A. Metcalf, Ginger Muzny, Donna Veeraraghavan, Narayanan Grove, Megan Shete, Sanjay Wallace, Stephanie Milewicz, Dianna Hanchard, Neil Lupski, James R. Hashmi, Syed Shahrukh Gupta-Malhotra, Monesha |
author_sort | Polfus, Linda M. |
collection | PubMed |
description | To comprehensively evaluate a European–American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine. |
format | Online Article Text |
id | pubmed-5111009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51110092016-11-29 Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome Polfus, Linda M. Boerwinkle, Eric Gibbs, Richard A. Metcalf, Ginger Muzny, Donna Veeraraghavan, Narayanan Grove, Megan Shete, Sanjay Wallace, Stephanie Milewicz, Dianna Hanchard, Neil Lupski, James R. Hashmi, Syed Shahrukh Gupta-Malhotra, Monesha Cold Spring Harb Mol Case Stud Research Report To comprehensively evaluate a European–American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine. Cold Spring Harbor Laboratory Press 2016-11 /pmc/articles/PMC5111009/ /pubmed/27900368 http://dx.doi.org/10.1101/mcs.a001255 Text en © 2016 Polfus et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. |
spellingShingle | Research Report Polfus, Linda M. Boerwinkle, Eric Gibbs, Richard A. Metcalf, Ginger Muzny, Donna Veeraraghavan, Narayanan Grove, Megan Shete, Sanjay Wallace, Stephanie Milewicz, Dianna Hanchard, Neil Lupski, James R. Hashmi, Syed Shahrukh Gupta-Malhotra, Monesha Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title | Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title_full | Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title_fullStr | Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title_full_unstemmed | Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title_short | Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome |
title_sort | whole-exome sequencing reveals an inherited r566x mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of liddle syndrome |
topic | Research Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111009/ https://www.ncbi.nlm.nih.gov/pubmed/27900368 http://dx.doi.org/10.1101/mcs.a001255 |
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