HSAN-2A

Genetic Context

HGNC-Approved Gene Symbol

WNK1

Gene Full Name

WNK lysine deficient protein kinase 1

Chromosome

12p13.33

Zygosity of Responsible Variant

Homozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Complete loss

Confidence:
High

Prediction:
The literature predicts a biallelic loss-of-function mechanism for HSAN-2A: recessive truncating variants cluster in HSN2, the nervous-system-specific exon of WNK1, and remove the neuronal isoform while leaving the ubiquitously expressed kinase intact. Both copies of that isoform must be lost before disease appears. Restored wild-type is predicted to rescue. Separate WNK1 alleles that raise kinase signaling cause pseudohypoaldosteronism type II, a hypertension disorder, so the two directions of effect at this locus give unrelated diseases.

Rationale:
Because the truncations fall in an exon used only by the neuronal transcript, the deficit is confined to the WNK1/HSN2 isoform, which explains why single-allele carriers are unaffected and why the kinase's renal functions are spared. Gain-of-function WNK1 alleles at the same locus drive hypertension instead, making direction of effect rather than the gene the determinant of phenotype.

ClinVar Pathogenic Variants

View WNK1 ClinVar Variants

ClinGen Curation

View WNK1 ClinGen Curation

GeneReviews®

HSAN-2A GeneReviews®

HSAN-2A OMIM Entry

HSAN-2A OMIM

WNK1 OMIM Entry

WNK1 OMIM