Pseudohypoaldosteronism Type II Panel

Pseudohypoaldosteronism type II (PHAII) is a rare monogenic disorder of renal electrolyte handling characterized by hypertension (due to increased renal salt reabsorption), hyperkalaemia (due to reduced renal K+ excretion, despite normal glomerular filtration and aldosterone secretion) and metabolic acidosis (due to reduced renal H+ secretion) (Wilson et al. 2001; Boyden et al. 2012). PHAII has a range of disease severity and age at disease onset. It has been sub-classified into five subtypes in terms of genetic locus, and individual causative genes have been identified for four subtypes.

Pseudohypoaldosteronism type IIB (OMIM# 614491) and IIC (OMIM# 614492) are caused by defects in WNK4 and WNK1 respectively, both of which encode WNK kinases. WNK kinases-related PHAII usually develops at an average age in the twenties to thirties and represents the less severe end of disease spectrum compared with that caused by mutations in KLHL3 and CUL3.

Pseudohypoaldosteronism type IID (OMIM# 614495) is caused by defects in the KLHL3 gene. KLHL3-related PHAII usually develops at an average age in the late twenties. The disease severity of KLHL3-related PHAII is more than that caused by WNK defects (WNK1 and WNK4) while much less than that caused by the CUL3 mutations.

Pseudohypoaldosteronism type IIE (OMIM# 614496) is caused by defects in CUL3. CUL3-related PHAII develops at an average age of nine and represents the most severe end of disease spectrum.

In pseudohypoaldosteronism type II (PHAII), the KLHL3-related subtype can be inherited in an autosomal dominant or recessive manner while the other three subtypes are autosomal dominant disorders caused by defects in WNK1, WNK4 or CUL3 (Wilson et al. 2001; Boyden et al. 2012; Louis-Dit-Picard et al. 2012).

KLHL3 has 15 coding exons that encode a BTB-domain-containing kelch protein, which plays a key role in salt, water, potassium, and pH homeostasis. To date, documented pathogenic KLHL3 variants include missense substitutions (majority), splicing and nonsense mutations, and small indels (Human Gene Mutation Database). Recessive KLHL3 mutations spread throughout the coding regions whereas dominant KLHL3 mutations apparently cluster in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding.

WNK1 has 28 coding exons that encode a serine-threonine protein kinase, which is a key regulator of blood pressure. To date, all documented PHAII-related WNK1 mutations are large deletions in intron 1 that led to an overexpression of the gene (Wilson et al. 2001).

WNK4 has 19 coding exons that encode a serine-threonine protein kinase, which is expressed exclusively in the kidney and plays a key role in salt, water, potassium, and pH homeostasis. To date, all documented pathogenic WNK4 mutations are missense substitutions (Human Gene Mutation Database).

PHAII-related CUL3 mutations have been found predominantly de novo. CUL3 has 16 coding exons that encode a member of the cullin protein family. Notably, to date, all documented PHAII-related CUL3 mutations result in an aberrant splicing of exon 9 regardless of mutation location within the vicinity of this region (Human Gene Mutation Database).

In a cohort of 52 pseudohypoaldosteronism type II (PHAII) families, 8 (~15%) and 16 families (~30%) were found to have recessive and dominant KLHL3 mutations, respectively (Boyden et al. 2012). In the same study, 5 families (about 10%) were found to have WNK4 mutations and 17 families (about 33%) were found to have CUL3 mutations (Boyden et al. 2012). No PHAII-related WNK1 mutations were found via Sanger sequencing because documented PHAII-causing WNK1 mutations are large deletions in intron 1, which cannot be detected by the current sequencing method (Wilson et al. 2001; Boyden et al. 2012).

The only documented PHAII-causing WNK1 pathogenic variants to date are large deletions in intron 1 (Wilson et al. 2001; Boyden et al. 2012).

No large deletions or duplications have been found in the CUL3, KLHL3 and WNK4 genes (Human Gene Mutation Database).

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).