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.
Previous studies have demonstrated PTEN mutations in a sizable proportion of individuals with ASD or mental retardation/developmental delays (MR/DD) and macrocephaly that do not have features of Cowden or Bannayan-Riley-Ruvalcaba syndrome.
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.
The identification of a novel frameshift variant of PTEN in a patient with "extreme" macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype.
The analysis of a panel of ASD-associated hereditary PTEN mutations revealed that most of them did not substantially abrogate PTEN activity in vivo, whereas most of PHTS-associated mutations did.
PTEN mutations have been more recently reported in children with macrocephaly and autism spectrum disorders or mental retardation, without other symptoms of PHTS.
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.
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>.
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.
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.
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.
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.
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.
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.
Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD).
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.