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.
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.
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 70130, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Polfus
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: Ginger
authors.initials: G
authors.lastname: Metcalf
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Veeraraghavan
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 70130, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Grove
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, The University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Shete
authors.affiliation: Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wallace
authors.affiliation: Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: Dianna
authors.initials: D
authors.lastname: Milewicz
authors.affiliation: Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Hanchard
authors.affiliation: Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 70130, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Pediatrics, Children's Memorial Hermann Hospital, The University of Texas Health Science Center, Houston, Texas, Medical School, Texas 77030, USA.
authors.forename: Syed Shahrukh
authors.initials: SS
authors.lastname: Hashmi
authors.affiliation: Department of Pediatric Cardiology, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA.
authors.forename: Monesha
authors.initials: M
authors.lastname: Gupta-Malhotra
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood; D000483:Alleles; D000584:Amiloride / Q000627:therapeutic use; D002675:Child, Preschool; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy; D007008:Hypokalemia / Q000188:drug therapy; D056929:Liddle Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D012083:Renin / Q000097:blood; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D053503:Epithelial Sodium Channels; D006852:Hydrochlorothiazide; D000450:Aldosterone; D000584:Amiloride; D012083:Renin
keywords: elevated diastolic blood pressure; elevated mean arterial pressure; elevated systolic blood pressure