Pseudohypoaldosteronism Type II via the CUL3 Gene

Pseudohypoaldosteronism type II (PHAII) is a rare monogenic disorder of renal electrolyte handling featured 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 of onset. Pseudohypoaldosteronism type IIE (OMIM# 614496) is caused by defects in CUL3. CUL3-related PHAII develops at an average age at nine and represents the most severe end of disease compared with that caused by mutations in WNK1, WNK4 and KLHL3.

Pseudohypoaldosteronism type II (PHAII) can be inherited in an autosomal dominant or recessive manner and has been associated with defects in four genes (WNK1, WNK4, KLHL3 and CUL3) (Wilson et al. 2001; Boyden et al. 2012). In particular, pseudohypoaldosteronism type IIE (PHA2E) is an autosomal dominant disorder caused by mutations (predominantly de novo) in the CUL3 gene. CUL3 has 16 coding exons that encode a member of the cullin protein family. Notably, to date, all documented PHAII-causing 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 including 126 affected subjects, 17 families (about 33%) were found to have CUL3 mutations (Boyden et al. 2012).

No large deletions or duplications have been found in CUL3 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CUL3 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).