Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism
| Autor: | So Lun Lee, Dingge Ying, Steven L.C. Pei, Mandy H.Y. Tsang, Winnie W.Y. Tso, Gordon K.C. Leung, Brian H.Y. Chung, Wanling Yang, Kit San Yeung, Christopher C.Y. Mak, Janice Jing Kun Ip |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Microcephaly PTEN Developmental delay Developmental Disabilities DNA Mutational Analysis medicine.disease_cause lcsh:RC346-429 Phosphatidylinositol 3-Kinases 0302 clinical medicine Medicine Macrocephaly Gene Regulatory Networks Protein Phosphatase 2 Megalencephaly Autism spectrum disorder Exome sequencing Genetics Mutation biology TOR Serine-Threonine Kinases MTOR Somatic mosaicism PPP2R5D Psychiatry and Mental health Female medicine.symptom Signal Transduction Class I Phosphatidylinositol 3-Kinases 03 medical and health sciences Germline mutation Developmental Neuroscience Exome Sequencing Humans Genetic Predisposition to Disease Molecular Biology Genetic Association Studies lcsh:Neurology. Diseases of the nervous system business.industry Research PTEN Phosphohydrolase Infant PIK3CA medicine.disease 030104 developmental biology biology.protein Autism business Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Molecular Autism, Vol 8, Iss 1, Pp 1-11 (2017) Molecular Autism |
| Popis: | Background Macrocephaly, 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. Methods We 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. Results We 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. Conclusion We 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 material The online version of this article (10.1186/s13229-017-0182-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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