SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes

Kidney Int. 2019 Jun;95(6):1494-1504. doi: 10.1016/j.kint.2019.01.025. Epub 2019 Mar 15.


Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.

Keywords: SON haploinsufficiency; gene expression; genetic mutations; pediatric nephrology; pre-mRNA splicing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Genetic Testing / methods*
  • HEK293 Cells
  • Haploinsufficiency*
  • Humans
  • Male
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / metabolism
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Splicing / genetics*
  • TRPP Cation Channels / genetics
  • Urogenital Abnormalities / diagnosis
  • Urogenital Abnormalities / genetics*
  • Vesico-Ureteral Reflux / diagnosis
  • Vesico-Ureteral Reflux / genetics*


  • DNA-Binding Proteins
  • Minor Histocompatibility Antigens
  • RNA Precursors
  • SON protein, human
  • TRPP Cation Channels
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein

Supplementary concepts

  • Cakut