Submission Details

WNK1 was first reported in relation to autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSAN2) in 2004 (Lafreniere et al., PMID: 15060842). Patients' symptoms began in infancy and they suffered from loss of touch and pain sensation in the distal limbs, leading to ulcerations and amputation of digits. Of note, this gene has also been implicated in autosomal dominant pseudohypoaldosteronism (PHA) type IIC (OMIM #614492). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, no overlapping phenotypes were identified in WNK1 patients with the two different diseases. The precise molecular mechanism leading to the diseases is still unknown; however, the two phenotypes are caused by mutations in different isoforms. HSAN2 variants affect a neuronal specific isoform and PHA affects a kidney specific isoform. Moreover, HSAN2 is caused by recessive LOF variants and PHA is caused by dominant intronic deletions leading to increased WNK1 expression. Therefore, the following disease entities have been split into two disease entities, HSAN2 (OMIM: 201300) and pseudohypoaudosteronism (OMIM:614492). Five loss-of-function (LOF) variants (nonsense and frameshift) have been reported in five probands with HSAN2 (PMIDs: 15060842, 15911806, 16636245