Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls.
While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness.
Importantly, this finding suggests that a germline PTEN variant might perturb the ASD or cancer networks differently, thus favoring one disease outcome at any one time.
Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability<sup>2,4,5</sup>.
Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder.
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.
Haploinsufficiency for PTEN is a cause of autism spectrum disorder and brain overgrowth; however, it is not known if PTEN mutations disrupt scaling across brain areas during development.
The tumour suppressor PTEN is frequently downregulated, mutated or lost in several types of tumours and congenital disorders including PHTS (PTEN Hamartoma Tumour Syndrome) and ASD (Autism Spectrum Disorder).
Our results lend insight into distinctive structural effects of germline PTEN mutations associated with PTEN-ASD vs. those associated with PTEN-cancer, potentially aiding in identification of the shared and separate molecular features that contribute to autism or cancer, thus, providing a deeper understanding of genotype-phenotype relationships for germline PTEN mutations.
Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer's disease, and autism spectrum disorders.
There is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology.
We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD.
Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients.
The data provide a basis for routine health checks for young children in Japan, including the follow-up management and possible screening of PTEN mutations in children with ASDs and macrocephaly.
We used viral-mediated molecular substitution of human PTEN into Pten knockout mouse neurons and assessed neuronal morphology to determine the functional impact of ASD-PTEN.
Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD).
In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice.
Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed.
Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.
Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory.