Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
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
_version_ 1782467789804535808
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
work_keys_str_mv AT polfuslindam wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT boerwinkleeric wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT gibbsricharda wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT metcalfginger wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT muznydonna wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT veeraraghavannarayanan wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT grovemegan wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT shetesanjay wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT wallacestephanie wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT milewiczdianna wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT hanchardneil wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT lupskijamesr wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT hashmisyedshahrukh wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome
AT guptamalhotramonesha wholeexomesequencingrevealsaninheritedr566xmutationoftheepithelialsodiumchannelbsubunitinacaseofearlyonsetphenotypeofliddlesyndrome