Pseudohypoaldosteronism Type I Panel

Pseudohypoaldosteronism type I (PHAI) is a group of disorders characterized by mineralocorticoid resistance in the kidneys and/or other mineralocorticoid target tissues. Patients have high levels of plasma aldosterone and renin, but also develop excessive salt wasting (Tajima et al. 2017. PubMed ID: 28804203). PHAI is classified into three forms. The systemic form results in severe neonatal onset life-threatening salt wasting in multiple organs including sweat glands, salivary glands, the colonic epithelium, and lungs. The renal form is characterized by aldosterone resistance that is restricted to the kidneys. The third form is a type of secondary PHA1 with an unknown mechanism, which is associated with urinary tract infections (UTI) and/or urinary tract malformations.

The systemic form of PHAI is an autosomal recessive disorder that is caused by defects in any one of three genes (SCNN1A, SCNN1B and SCNN1G) (Chang et al. 1996. PubMed ID: 8589714; Hansson et al. 1995. PubMed ID: 7550319). These three genes (each with 12 coding exons) encode the alpha, beta and gamma subunits of the epithelial sodium channel (ENaC), respectively. These amiloride-sensitive channels play a key role in electrolyte transportation across epithelia in many organs.

The renal form of PHAI is an autosomal dominant disorder that is caused by defects in the NR3C2 gene (Geller et al. 1998. PubMed ID: 9662404). The NR3C2 gene (eight coding exons) encodes the mineralocorticoid receptor, which is important in regulating the sodium level in the body.

Genetic defects spread throughout the SCNN1A, SCNN1B, SCNN1G and NR3C2 genes include missense and various truncating variants (nonsense, splicing variants and small deletions/insertions) (Human Gene Mutation Database). Gross deletions and duplications in these genes appear to be rare as only a few large deletions have been documented in SCNN1A, SCNN1B, and NR3C2 to date (Human Gene Mutation Database). Of note, de novo pathogenic variants are common in NR3C2 (Pujo et al. 2007. PubMed ID: 16972228).

In a multi-center European cohort of Pseudohypoaldosteronism type I (PHAI) patients, pathogenic NR3C2 variants were identified in 87% of kindreds with familial autosomal dominant PHAI and in 81% of patients with a sporadic renal presentation (Pujo et al. 2007. PubMed ID: 16972228).

The diagnostic rate of the systemic form of PHAI by testing the three genes SCNN1A, SCNN1B and SCNN1G in a large cohort of patients is unavailable because studies in the literature only include a limited number of cases.

Gross deletions and duplications in these genes appear to be rare as only a few large deletions have been documented in SCNN1A, SCNN1B, and NR3C2 to date (Human Gene Mutation Database). No large deletions or deletions have yet been found involving SCNN1G.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).