Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

Pediatr Nephrol. 2018 Mar;33(3):473-483. doi: 10.1007/s00467-017-3819-9. Epub 2017 Oct 23.


Background: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.

Methods: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort.

Results: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing.

Conclusions: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Keywords: EMP2; Familial nephrotic syndrome; Genetics; HLA-DQA1; Immunity; Podocyte; Steroid resistance; Steroid sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Glucocorticoids / therapeutic use*
  • HLA-DQ alpha-Chains / genetics*
  • Humans
  • Infant
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Mutation
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics*
  • Sequence Analysis, DNA / methods
  • Young Adult


  • EMP2 protein, human
  • Glucocorticoids
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • Membrane Glycoproteins