SCNN1A – Autosomal Recessive Pseudohypoaldosteronism Type IB1

Autosomal recessive pseudohypoaldosteronism type IB1 (PHA1B) is caused by biallelic loss-of-function variants in the epithelial sodium channel α-subunit gene SCNN1A. A 17-day-old Saudi female infant presenting with persistent hyperkalemia, hyponatremia, and metabolic acidosis was found to harbor a novel homozygous nonsense variant c.1522C>T (p.Arg508Ter) in SCNN1A, consistent with PHA1B diagnosis (PMID:39295704).

Genetic evidence for SCNN1A in PHA1B includes 17 affected individuals across five unrelated pedigrees, all showing autosomal recessive inheritance. Two siblings in one consanguineous family carried a homozygous missense variant c.398G>A (p.Cys133Tyr) with clinical salt wasting (PMID:12376807); a preterm neonate was homozygous for c.727T>C (p.Ser243Pro) and displayed transient salt loss (PMID:21653223); twelve patients from four families carried p.Phe226Cys, presenting mild and transient PHA1B (PMID:37134141); and a Somali neonate with c.1684T>C (p.Ser562Pro) showed systemic PHA1 (PMID:18547339).

Segregation analysis confirmed homozygous variants cosegregating with disease in two families, and all probands were homozygous or compound heterozygous for SCNN1A variants, supporting autosomal recessive transmission.

Functional assays in Xenopus laevis oocytes demonstrate drastic reductions (≥80%) in ENaC current for p.Cys133Tyr, p.Ser243Pro, p.Phe226Cys, and truncating p.Arg508Ter variants, and Western blot studies show reduced ENaC protein expression for p.Phe226Cys, indicating a loss-of-function mechanism concordant with human salt-wasting phenotypes.

No conflicting evidence has been reported for SCNN1A involvement in PHA1B. The collective genetic and functional data fulfill ClinGen criteria for a Strong gene–disease association between SCNN1A and PHA1B.

Key Take-home: Biallelic LOF variants in SCNN1A cause autosomal recessive PHA1B; genetic testing for SCNN1A should be integrated into diagnostic panels for neonatal salt-wasting syndromes to guide timely management.

References

• Cureus | 2024 | Pseudohypoaldosteronism Type 1b in a Saudi Female Infant Due to Homozygous Variant Gene Mutation in SCNN1A: A Case Report. PMID:39295704
• Pediatric Nephrology • 2002 • A novel mutation of the epithelial Na+ channel causes type 1 pseudohypoaldosteronism. PMID:12376807
• American Journal of Physiology. Endocrinology and Metabolism • 2011 • A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1. PMID:21653223
• Clinical Endocrinology • 2023 • A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene. PMID:37134141
• Clinical Endocrinology • 2009 • Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel. PMID:18547339

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