Steroid-Resistant Nephrotic Syndrome and XX Female Gonadal Dysgenesis via the NUP107 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. Defects in the nuclear pore complex subunit NUP107 cause autosomal recessive early-childhood-onset SRNS (Miyake et al. 2015).

A homozygous missense NUP107 variant has also been reported to cause XX female gonadal dysgenesis (Weinberg-Shukron et al. 2015). The disease is characterized by underdeveloped and dysfunctional ovaries, lack of spontaneous pubertal development, uterine hypoplasia, primary amenorrhea, and hypergonadotropic hypogonadism.

NUP107-associated nephrotic syndrome is inherited in an autosomal recessive manner (Miyake et al. 2015). The NUP107 gene (28 coding exons) encodes a nuclear pore complex subunit. The nuclear pore complex plays important roles in nucleocytoplasmic transport, nuclear framework, and gene regulation. Genetic defects documented to date in NUP107 include missense, nonsense, splicing variants and small indels (Human Gene Mutation Database). No large deletions or duplications have been reported. Of note, a missense variant in a homozygous state in NUP107 has been reported to cause XX female gonadal dysgenesis (Weinberg-Shukron et al. 2015).

Biallelic NUP107 pathogenic variants were found in five of 18 unrelated families with early-onset SRNS without any known genetic causes in 27 known Steroid-Resistant Nephrotic Syndrome causative genes (Miyake et al. 2015).

To date, only one NUP107 missense pathogenic variant has been reported to cause XX female gonadal dysgenesis (Weinberg-Shukron et al. 2015).

This test provides full coverage of all coding exons of the NUP107 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).