Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY/ABSTRACT Germline PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), a hereditary overgrowth and cancer predisposition disorder. Besides being a classical tumor suppressor gene associated with cancer, PTEN mutations are one of the most common causes of neurodevelopmental disorders, including autism spectrum disorder (ASD) and developmental delay (DD). However, it is not known which specific PHTS individual will develop ASD/DD, and importantly, whether all children with PHTS and ASD/DD grow up to have identical cancer risks as non-ASD/DD PHTS. The broad over-arching objective of this proposal is to systematically characterise the modifier landscape of individuals with PHTS in order to ultimately shift current research and clinical practice paradigms from population-level probabilities towards more precise individual-level disease risk probabilities. Based on the current knowledge gaps and proof-of-principle data, the central hypothesis is that interactions of germline PTEN variation with other pertinent measurable biological factors, such as germline genomic modifiers or metabolic differences, provide more precise risk estimates of ASD/DD and possibly, comorbid cancer in PHTS at the individual level. This hypothesis will be tested through three specific aims: (Aim 1) To identify metabolomic markers of ASD/DD and cancer risk in PHTS patient-derived plasma and lymphoblastoid cell lines; (Aim 2) To characterize genomic markers of ASD/DD and cancer risk in PHTS via multimodal phenotype-driven genomic analyses including copy number variation analysis, family-based whole-genome sequencing, and genome-wide derivation of polygenic risk scores; (Aim 3) To generate a predictive model of ASD/DD and cancer risk in PHTS including translational methods to facilitate clinical adoption for individual patient risk stratification. This patient-focused research will rely on an existing uniformly phenotyped PHTS cohort and continuing prospective accrual of individuals harboring germline PTEN mutations. The proposed research aligns with the NICHD Priorities and the Interagency Autism Coordinating Committee strategic plan for ASD in that the priority is (1) to understand genetic syndromes associated with ASD and the co-occurring medical and mental health conditions associated with such disorders; (2) to identify reliable markers to predict for ASD within PHTS in a timely manner, since earliest interventions lead to improved outcomes in ASD; (3) to understand the biology of autism through investigating metabolomic and genomic markers and importantly, integrating these factors through predictive model development. The proposed research is innovative because in addition to studying a monogenic (less heterogeneous) and deeply/uniformly phenotyped group of individuals with PTEN-ASD/DD, this proposal goes beyond observational epidemiological interrogation into investigating underlying metabolomic and genomic factors that contribute first to altered ASD/DD and then comorbid cancer risks in individuals with ASD/DD. Upon conclusion, in addition to discovery science, this application is projected to result in predictive methods that clinicians can adopt at the point-of-care.
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