Steroid-Resistant Nephrotic Syndrome (SRNS) via the PLCE1 Gene

Nephrotic syndrome is a genetically heterogeneous disease defined by proteinuria, hypoalbuminemia, hyperlipidemia, and edema (Benoit et al. 2010; Santín et al. 2011; Saleem 2012). Approximately 20% of cases are steroid-resistant nephrotic syndrome (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 course of SRNS varies greatly with a wide range of age at onset from birth to adulthood. Defects in the PLCE1 gene cause early-onset autosomal recessive SRNS with DMS or FSGS commonly seen on renal biopsy (Hinkes et al. 2006; Gbadegesin et al. 2008; Boyer et al. 2010).

Recessive PLCE1 pathogenic variants represent the major cause of SRNS with DMS (Gbadegesin et al. 2008; Boyer et al. 2010). The PLCE1 gene (31 coding exons) encodes phospholipase C epsilon 1 (PLCε1), which is a member of the phospholipase family of enzymes that catalyzes the hydrolysis of polyphosphoinositides to generate second messengers (Hinkes et al. 2006). To date, documented genetic defects of PLCE1 include missense, nonsense, splicing mutations, small indels and large deletions (rare) (Human Gene Mutation Database).

Recessive PLCE1 pathogenic variants were identified in 10/35 (28.6%) families affected by isolated (non-syndromic) DMS (Gbadegesin et al. 2008). In another study, recessive PLCE1 pathogenic variants were found in affected individuals from 12 (18%) of 68 families with SRNS and 3 (7%) of 44 patients without a family history indication (Boyer et al. 2010).

This test provides full coverage of all coding exons of the PLCE1 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).