Nephrotic Syndrome or Palmoplantar Keratoderma and Woolly Hair via the KANK2 Gene

Nephrotic syndrome (NS) is a genetically heterogeneous disease defined by proteinuria, hypoalbuminemia, hyperlipidemia, and edema (Benoit et al. 2010; Santín et al. 2011; Saleem 2013). NS in young adults and children is classified into steroid-sensitive NS (SSNS) versus steroid-resistant NS (SRNS) in terms of its response to a standardized steroid therapy. Approximately 20% of cases are SRNS, characterized by resistance to steroid treatment and rapid progression to end-stage renal failure. The prevalent histological feature of SRNS is focal segmental glomerulosclerosis (FSGS), which has been seen in approximately 60% of SRNS cases. Diffuse mesangial sclerosis (DMS) is the other important histological feature associated with SRNS. The clinical courses of NS vary greatly with a wide range of age at onset from birth to adulthood.

The other KANK2-associated disorder is autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy (dyspnea, syncope or sudden death) (Ramot et al. 2014). Clinical features include leukonychia of fingernails, striate keratoderma of palmar skin, keratoderma of plantar skin, sparse and woolly scalp hair, and deep sulcus and bulbous appearance of toes.

KANK2-associated nephrotic syndrome or keratoderma and woolly hair is inherited in an autosomal recessive manner (Gee et al. 2015; Ramot et al. 2014). The KANK2 gene (11 coding exons) encodes kidney ankyrin repeat-containing protein 2. The KANK gene family plays important roles in podocyte function likely through the RHO GTPase signaling pathway. Genetic defects documented to date in KANK2 include three missense pathogenic variants (Human Gene Mutation Database).

In a targeted gene sequencing study of 576 individuals with steroid sensitive NS (SSNS) and 542 individuals with SRNS, two homozygous missense pathogenic variants in KANK2 were found (Gee et al. 2015).

To date, only one missense pathogenic variant in KANK2 has been reported in two consanguineous families with palmoplantar keratoderma and woolly hair (Ramot et al. 2014).

This test provides full coverage of all coding exons of the KANK2 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).