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Keywords: Autism; Cancer; Intellectual and developmental disability; Cancer syndromes; Molecular pathophysiology

Accredited session: 0.25

F. Meili 1,2,3; K. Post 1,2,3; M. Belmadani 1,4; P. Ganguly 1,2,3; R. Dingwall 1,2,3; T. McDiarmid 1,2,5; C. Harrington 1,2,3; M. Edwards 1,2,3; B. Young 1,3; A. Niciforovic 1,2,3; B. Callahan 1,4; S. Rogic 1,4; W. Meyers 1,2,3; A. Cau 1,2,3; T. O'Connor 1,2,3; C. Rankin 1,2,5; S.X. Bamji 1,2,3; D.W. Allen 1,2,3; C. Loewen 1,3; P. Pavlidis 1,4; K. Haas 1,2,3

1) University of British Columbia; 2) Djavad Mowafaghian Centre for Brain Health; 3) Department of Cellular and Physiological Sciences; 4) Department of Psychiatry; 5) Department of Psychology

Functional variomics promises to provide the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on the assays employed to adequately evaluate mutation impact on all aspects of a protein’s function. In order to fully assess the impact of 104 missense (MS) and nonsense (NS) variants of PTEN (phosphatase and tensin homologue deleted on chromosome 10) associated with autism spectrum disorder (ASD), somatic cancer and PTEN hamartoma tumor syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning phylogeny, including yeast, fly, worm, rat primary neuronal culture, and a human cell line. Our approach allows correlation of phenotypes in assays ranging from molecular function to neuronal morphogenesis and behavior. Most assays strongly correlate with measures of lipid phosphatase function, while others implicate additional PTEN functions. We find that protein instability is a major mechanism of dysfunction for variants altering amino acids across the entire protein structure. Other variants, located in discrete functional domains including the N-terminus substrate binding and the catalytic domains exhibited impacts ranging from loss of function to antimorphic/dominant negative phenotypes independent of effects on stability. Results indicate that 31 of the 48 variants tested from ASD individuals are likely pathogenic and 2 are likely benign and not causal.