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

Nephrotic syndrome (NS) is a genetically heterogeneous disease defined by proteinuria, hypoalbuminemia, hyperlipidemia, and edema (Benoit et al. 2010. PubMed ID: 20333530; Santín et al. 2011. PubMed ID: 21415313; Preston et al. 2019. PubMed ID: 29181713). It is the most common glomerular disease in children. Nephrotic syndrome in young adults and children is classified into steroid-sensitive NS (SSNS) versus steroid-resistant NS (SRNS) in terms of its response to 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. Hereditary FSGS can be either limited to the kidney or syndromic with features in other systems. Diffuse mesangial sclerosis (DMS) is the other important histological feature associated with SRNS. SRNS accounts for ~11% of early-onset chronic kidney disease (Vivante and Hildebrandt. 2016. PubMed ID: 26750453). The clinical courses of NS vary greatly with a wide range of age at onset from birth to adulthood. A conclusive molecular diagnosis is necessary for better personalized treatment and accurate genetic counselling.

Extrarenal manifestations in patients with SRNS caused by defects in the AVIL gene have been reported to include retinal dystrophy, deafness, cataract, microcephaly, intellectual disability, and short stature (Rao et al. 2017. PubMed ID: 29058690). However, it is uncertain that these features are common for AVIL-related SRNS due to limited cases.

Steroid-resistant nephrotic syndrome (SRNS) represents a clinically and genetically heterogeneous group of autosomal dominant, autosomal recessive or X-linked disorders. The AVIL gene falls into the group of autosomal recessive inheritance and is one of the minor causative genes for the disease (Rao et al. 2017. PubMed ID: 29058690).

Loss-of-function is the underlying mechanism of AVIL for SRNS. This gene encodes the actin-binding protein advillin that is involved in podocyte cytoskeleton architecture. To date, only three missense and one truncating variant have been reported (Human Gene Mutation Database; Rao et al. 2017. PubMed ID: 29058690). Large deletions and duplications have not been reported in this gene. De novo variants are presumably rare.

AVIL has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). To date, no animal models have been reported (Rao et al. 2017. PubMed ID: 29058690).  

In a cohort of approximately 800 individuals with SRNS worldwide, two unrelated patients (~0.25%) were reported to have compound heterozygous pathogenic variants in the AVIL gene (Rao et al. 2017. PubMed ID: 29058690).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

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