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

Overview of attention for article published in Molecular Autism, December 2017
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Title
Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism
Published in
Molecular Autism, December 2017
DOI 10.1186/s13229-017-0182-4
Pubmed ID
Authors

Kit San Yeung, Winnie Wan Yee Tso, Janice Jing Kun Ip, Christopher Chun Yu Mak, Gordon Ka Chun Leung, Mandy Ho Yin Tsang, Dingge Ying, Steven Lim Cho Pei, So Lun Lee, Wanling Yang, Brian Hon-Yin Chung

Abstract

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. 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. 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. 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.

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Mendeley readers

The data shown below were compiled from readership statistics for 43 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 43 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 10 23%
Researcher 6 14%
Student > Bachelor 6 14%
Other 5 12%
Student > Master 5 12%
Other 11 26%
Readers by discipline Count As %
Agricultural and Biological Sciences 9 21%
Biochemistry, Genetics and Molecular Biology 9 21%
Neuroscience 8 19%
Unspecified 6 14%
Medicine and Dentistry 6 14%
Other 5 12%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 July 2018.
All research outputs
#10,613,212
of 13,331,792 outputs
Outputs from Molecular Autism
#395
of 422 outputs
Outputs of similar age
#277,478
of 385,469 outputs
Outputs of similar age from Molecular Autism
#23
of 26 outputs
Altmetric has tracked 13,331,792 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 422 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 30.1. This one is in the 2nd percentile – i.e., 2% of its peers scored the same or lower than it.
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