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Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001255.

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.

Author information

1
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 70130, USA.
2
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 70130, USA;; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
4
Department of Biostatistics, MD Anderson Cancer Center, The University of Texas Health Science Center, Houston, Texas 77030, USA.
5
Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center, Houston, Texas 77030, USA.
6
Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 70130, USA.
7
Department of Pediatrics, Children's Memorial Hermann Hospital, The University of Texas Health Science Center, Houston, Texas, Medical School, Texas 77030, USA.
8
Department of Pediatric Cardiology, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA.

Abstract

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.

KEYWORDS:

elevated diastolic blood pressure; elevated mean arterial pressure; elevated systolic blood pressure

PMID:
27900368
PMCID:
PMC5111009
DOI:
10.1101/mcs.a001255
[Indexed for MEDLINE]
Free PMC Article

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