Aldosterone plays a critical role in sodium homeostasis by binding to the mineralocorticoid receptor promoting sodium retention. It increases the expression of epithelial sodium channels (ENaC) and sodium-potassium ATPases in the renal distal tubules and collecting ducts. Defects in aldosterone synthesis lead to hyponatremia, hyperkalemia, hyperreninemia, metabolic acidosis, and hypovolemia.
We present a 7-year-old boy with holoprosencephaly, dysmorphic features, and short stature presenting with persistent hyponatremia since birth and occasional hypokalemia and hyporeninemia. Initial whole exome sequencing (WES) identified a novel in-frame SHH variant, NM_000193.4:c.755_757del (p.Phe252del); possible aldosterone deficiency due to adrenocortical hypoplasia caused by the SHH variant did not fully explain the patient's clinical presentation, prompting further investigation.
Deep analysis of the WES data revealed a second variant of unknown significance in the SCNN1G gene affecting the γ-ENaC subunit, namely NM_001039.4.1904 C > T (p.Ala635Val), which was previously unreported in association with a clinical phenotype. Electrophysiological studies of the amiloride-sensitive current before and after trypsin exposure showed that the γ-ENaC-A635V mutation reduced the amiloride-sensitive sodium current by approximately 30%. The trypsin experiments suggested a lower channel open probability and a reduced inward sodium current through the ENaC.
These findings indicate that the A635 residue participates in channel function, with γ-Α635V leading to decreased sodium reabsorption. This case underscores the importance of reevaluating genetic data to understand complex clinical presentations and identifies a new potential pathogenic variant affecting sodium homeostasis. The case illustrates how genetic variants with contrasting effects on a physiological loop along with functional changes due to development and age may be hard to interpret.