Mutations in PIK3R1 cause SHORT syndrome

David A. Dyment*, Amanda C. Smith, Diana Alcantara, Jeremy A. Schwartzentruber, Lina Basel-Vanagaite, Cynthia J. Curry, I. Karen Temple, William Reardon, Sahar Mansour, Mushfequr R. Haq, Rodney Gilbert, Ordan J. Lehmann, Megan R. Vanstone, Chandree L. Beaulieu, Jacek Majewski, Dennis E. Bulman, Mark O'Driscoll, Kym M. Boycott, A. Micheil Innes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

153 Scopus citations


SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906-1907insC (p.Asn636Thrfs18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906-1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.

Original languageEnglish
Pages (from-to)158-166
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 11 Jul 2013
Externally publishedYes


FundersFunder number
Senior Cancer Research UK
Genome Canada
Government of Canada
Canadian Institutes of Health Research
Ontario Genomics InstituteOGI-049
Medical Research Council
Cancer Research UK
Leukaemia and Lymphoma Research


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