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

Jung-Hyun Kim, Eun Young Park, David Chitayat, David L. Stachura, Jorg Schaper, Kristin Lindstrom, Tamison Jewett, Dagmar Wieczorek, Jos M. Draaisma, Margje Sinnema, Christianne Hoeberigs, Maja Hempel, Kristine K. Bachman, Andrea H. Seeley, Joshua K. Stone, Hyun Kyung Kong, Lana Vukadin, Alexander Richard, Deepali N. Shinde, Kirsty McWalterYue Cindy Si, Ganka Douglas, Ssang-Taek Lim, Lisenka E. L. M. Vissers, Mathieu Lemaire*, Eun-Young Erin Ahn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1494-1504
Number of pages11
JournalKidney International
Issue number6
Publication statusPublished - Jun 2019


  • gene expression
  • genetic mutations
  • pediatric nephrology
  • pre-mRNA splicing
  • SON haploinsufficiency
  • PKD1


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