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.

Neonatal presentation of a patient with Liddle syndrome, South Africa

“…Furthermore, mutation studies permit clinicians to advocate for family screening based on the proband to identify carriers. 14 …”

“…Genetic testing (including whole exome sequencing) should be performed, when possible, to identify mutations in patients with suspected secondary hypertension and unusual presentation. 14 …”

A Family with Liddle Syndrome Caused by a Novel Stop-Gain Mutation in the γ Subunit of Epithelial Sodium Channels

“…Liddle syndrome usually presents in late childhood and adolescence, but it can also occur even in early childhood [3, 4]. It is a form of monogenic hypertension caused by activating germline variants in genes encoding for ENaC subunits [1].…”