PTEN Mutation in Children with Autism and Macrocephaly: A Case Report of Two Previously Unrecognized Promoter Region Mutations

Thursday, May 14, 2015: 5:30 PM-7:00 PM
Imperial Ballroom (Grand America Hotel)
D. U. Menon, Kennedy Krieger Institute, Baltimore, MD

Autism is characterized by impairment in communication, social interaction, insistence on sameness and restricted repetitive actions & stereotyped movements. 20% of children with Autism Spectrum Disorders (ASD) have macrocephaly and 10% are associated with known genetic syndromes.
Phosphatase and tensin analogue on chromosome 10q23.3 gene (PTEN), is a tumor suppressor gene which encodes a dual specificity Phosphatase ,that negatively regulates the PI3K/AKT pathway. PTEN germline mutations have been associated with macrocephaly, seizures, tumors and mental retardation with four hamartomous syndromes Recent work by Butler et al (2005) and Goffin et al (2001) have shown the association of PTEN germline mutation in patients with macrocephaly and ASD.

Objectives: Prevalence of PTEN mutation in a clinical population of ADOS proven cases of autism spectrum disorder (ASD) and relative and absolute macrocephaly (>2SD above mean HC for age and sex).
Mutation identification for these patients by DNA sequencing of the promoter and coding regions of the PTEN gene.
Phenotype-genotype correlation of subjects with ASD and PTEN mutation  


Study eligible participants in the Autism Clinic  and the JHH Genetics clinics were enrolled after obtaining signed informed . Parents of eligible subjects completed intake questionnaires (SRS) ,the children were administered the Mullen Scales of Early Learning or the subtests of the Stanford Binet . Children over age 12 months of age were administered the Autism Diagnostic Observation Schedule (ADOS) .6 ml-10 ml  of blood  was drawn for this assessment in children with ASD who are above the age of 18 months  and were sent to  the DNA Diagnostic Center at JHH. Genomic DNA (gDNA) was isolated from the blood sample within 24 hours of. A portion of the gDNA was diluted and used for PCR amplification of the promoter region and coding exons of the PTEN gene and were then sequenced bi-directionally and compared to normal control reference sequence in silico to identify mutations
Medical records for subjects with positive PTEN mutation were reviewed for an initial correlation of potentially pathological mutations, and cognitive and behavioral phenotype that may be associated with the underlying mutation.


Five out of 25 subjects were found to have mutations in the promoter region of the PTEN gene , of which three were previously reported rare PTEN variants, and  2 had not been previously reported in the scientific literature.


This is a case report of two new variants in the PTEN mutations in a subset of children with ASD and macrocephaly and indicates that PTEN mutation screening should be done in the initial diagnostic workup of children with macrocephaly and autism.

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See more of: Genetics