Liddle Syndrome and Autosomal Recessive Pseudohypoaldosteronism Type 1 via the SCNN1G Gene

Liddle syndrome (OMIM #177200) is an inherited disorder of sodium reabsorption in the renal distal tubules characterized by severe early onset of hypertension with hypokalemia, metabolic alkalosis, low plasma renin activity, and suppressed aldosterone secretion (Botero-Velez et al. N Engl J Med 330(3):178-181, 1994; Shimkets et al. Cell 79(3):407-414, 1994). Untreated hypertension in these patients can progress with age to renal failure, heart disease or stroke.

Autosomal recessive pseudohypoaldosteronism type 1 (PHA1; OMIM #264350) is a multi-organ life-threatening disorder characterized by severe neonatal onset salt wasting and high concentrations of sodium in sweat, stool, and saliva (Chang et al. Nat Genet 12(3):248-253, 1996; Scheinman et al. N Engl J Med 340(15):1177-1187, 1999). Clinical features include hyponatremia, hyperkalaemia, metabolic acidosis, unresponsiveness to mineralocorticoid hormones, and increased plasma renin activity with high serum aldosterone concentrations. Compared with autosomal dominant PHA1, the recessive form of the disease is a more severe systemic condition with persistence into adulthood. Some patients had recurrent respiratory problems (Chang et al., 1996; Schaedel et al. J Pediatr 135(6):739-745, 1999). Genetic confirmation is essential for distinguishing autosomal recessive PHA1 from cystic fibrosis-like disease (Sheridan et al. Hum Mol Genet 14(22):3493-3498, 2005; Azad et al. Hum Mutat 30(7):1093-1103, 2009; Mora-Lopez et al. Eur J Pediatr 171(6):997-1000, 2012).

Autosomal recessive PHA1 can be caused by mutations in any one of the three genes (SCNN1A, SCNN1B and SCNN1G) encoding the epithelial sodium channel (ENaC) while Liddle syndrome is an autosomal dominant disorder caused by mutations in SCNN1B or SCNN1G (Shimkets et al., 1994; Hansson et al. Nat Genet 11(1):76-82, 1995; Chang et al., 1996). These amiloride-sensitive channels play a key role in electrolyte transportation across epithelia in many organs. SCNN1G has 12 coding exons that encode the gamma subunit of ENaC. Genetic defects located throughout the SCNN1G gene include missense, nonsense, splicing mutations and small deletion/insertions. Gross deletions and duplications within the SCNN1G gene have not been reported (Human Gene Mutation Database).

SCNN1G mutation detection rate in a large cohort of patients is unavailable because these mutations have been only reported in individual cases. Mutations in SCNN1G are less common than mutations in SCNN1A and SCNN1B (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SCNN1G gene 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 full 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).