Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

Abstract

BackgroundMacrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients.MethodsWe performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR.ResultsWe identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly.ConclusionWe identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder.Electronic supplementary materialThe online version of this article (10.1186/s13229-017-0182-4) contains supplementary material, which is available to authorized users.

PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

“…Protein Phosphatase 2 Regulatory Subunit B Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay is a disorder that mainly occurs due to de novo mutations in the PPP2R5D gene [1][2][3][4]. The PPP2R5D gene codes for one of the isoforms of the regulatory subunit family B56, of the heteromeric enzyme protein phosphatase 2A (PP2A) [5].…”

“…The PPP2R5D gene codes for one of the isoforms of the regulatory subunit family B56, of the heteromeric enzyme protein phosphatase 2A (PP2A) [5]. Mutations in PPP2R5D are associated with neurodevelopmental delay, autism spectrum disorder (ASD), ID, behavioral challenges, and so forth, which are seen soon after birth [1][2][3][4]6]. In the United States, this disorder is currently referred to as Jordan's syndrome, named after Jordan Lang, the first child diagnosed in the United States [7].…”

Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

“…The primary aim is to identify somatic mutations for genetic overgrowth syndrome. 14 Detailed classification was listed in Table S3.…”

“…If the clinical geneticist was suspicious of somatic mosaicism in the subject, 13,14 buccal mucosa was also obtained as a germline source of DNA. If the clinical geneticist was suspicious of somatic mosaicism in the subject, 13,14 buccal mucosa was also obtained as a germline source of DNA.…”

“…Genomic DNA was obtained from the peripheral blood using Qiagen Blood Mini Kit (Qiagen). If the clinical geneticist was suspicious of somatic mosaicism in the subject, 13,14 buccal mucosa was also obtained as a germline source of DNA.…”