Pseudohypoaldosteronism Type II via the KLHL3 Gene

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. Pseudohypoaldosteronism type IID (OMIM# 614495) is caused by defects in the KLHL3 gene. KLHL3-related PHAII usually develops at an average age of 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.

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 are 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.

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).

No large deletions or duplications have been found in KLHL3 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the KLHL3 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).