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Abstract: TH-PO702

Mutations in PIK3C2A Cause Syndromic Short Stature Associated with Eye, Skeletal, and Renal Involvement

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Schueler, Markus, University of Erlangen-Nuernberg, Erlangen, Germany
  • Chen, Anlu, Case Western Reserve Univ, Cleveland, Ohio, United States
  • Tiosano, Dov, Mayer Children`s Hospital, Haifa, Israel
  • Baris, Hagit N., Rambam Health Care Campus, Haifa, Israel
  • Hitzert, Marrit, University Medical Center Groningen, Groningen, Netherlands
  • Mory, Adi, Rambam health care campus, Haifa, Israel
  • Knaup, Karl, University of Erlangen-Nuremberg, Erlangen, Germany
  • Roepman, Ronald, Radboud University Medical Center, Nijmegen, Netherlands
  • Pfundt, Rolph, RadboudUMC, Nijmegen, Netherlands
  • Aslanyan, Mariam, Radboud Institut for Molecular Life Science, Nijmegen, Netherlands
  • Buchner, David A., Case Western Reserve University, Cleveland, Ohio, United States
  • Wiesener, Michael Sean, University Hospital Erlangen, Erlangen, Germany

PIK3C2A is a member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI). Class II PI3Ks has been attributed a wide-range of biological functions including, angiogenesis, cellular signaling, endosomal trafficking, exocytosis as well as ciliary formation and function. However, its function is still poorly understood. Identifying the genetic basis of Mendelian diseases provide insight into gene function, susceptibility to disease and can improve clinical care.


We performed whole exome sequencing in three independent consanguineous families to identify the underlying single-gene disease-causing mutation. We then obtained dermal fibroblasts from skin biopsies of the affected individual and healthy controls for molecular studies.


We identified three homozygous protein-truncating mutations in the gene PIK3C2A in five children from independent consanguineous families. The affected individuals show a considerable overlapping phenotype including cataract, skeletal abnormalities, hearing loss and renal involvement among other features. Molecular data of patient-derived fibroblasts were consistent with loss of PIK3C2A function as evidenced by the lack of PIK3C2A protein. In addition we demonstrate that the PIK3C2A deficiency caused impaired cilia formation, decreased levels of PI in primary cilia, and altered the phosphorylation status of Akt, GSK3beta as well as the expression level of AXIN2.


We demonstrate that loss-of-function mutations in PIK3C2A resulting in a novel syndrome consisting of short stature, cataracts, hearing loss, skeletal abnormalities and renal involvement. This discovery, together with studies of other disorders of PI metabolism, will enable future studies to discover the pathophysiological mechanism basis of this syndrome to better understand the role of PIK3C2A.