Submission Details

Autosomal recessive

07/30/2019

The NPHS2 gene is located on chromosome 1 at 1q25.2 and encodes NPHS2 stomatin family member, podocin. Podocin is expressed in the kidney, specifically in podocytes of glomeruli where it is localised at the slit diaphragm. Podocin interacts with nephrin and mediates glomerular permeability and filtration and plays a role in podocyte cell signaling. NPHS2 was first reported in relation to autosomal recessive nephrotic syndrome in 2000 (10742096: Boute et al. 2000). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight unique variants have been reported in seven probands with nephrotic syndrome from three studies in the literature (10742096: Boute et al. 2000; 23242530: Kerti et al. 2013; 17371932: Hinkes et al. 2007). These included two missense variants, a nonsense variant and four small indels resulting in frameshift. Variants in this gene segregated with disease in at least five additional family members across three families. More genetic evidence is available in the literature, but the maximum score for this category has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the specific expression of podocin in the glomeruli of the kidney (10742096: Boute et al. 2000), demonstration of interaction of with nephrin (variants in which are also known to cause nephrotic syndrome) (14570703: Huber et al. 2003), and a mouse model which recapitulates clinical and histological features of the disease (29049388: Tabatabaeifar et al. 2017). In summary, NPHS2 is definitively associated with nephrotic syndrome.

10742096 23242530 17371932 14570703 29049388