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Open Access 01-12-2014 | Research

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Authors: Abha R Gupta, Michelle Pirruccello, Feng Cheng, Hyo Jung Kang, Thomas V Fernandez, Jeremy M Baskin, Murim Choi, Li Liu, Adife Gulhan Ercan-Sencicek, John D Murdoch, Lambertus Klei, Benjamin M Neale, Daniel Franjic, Mark J Daly, Richard P Lifton, Pietro De Camilli, Hongyu Zhao, Nenad Šestan, Matthew W State

Published in: Molecular Autism | Issue 1/2014

Abstract

Background

Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD.

Methods

We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue.

Results

Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10⁻¹⁶, Wilcoxon test) with a module of genes significantly associated with ASD.

Conclusions

Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism.

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Title: Rare deleterious mutations of the gene EFR3A in autism spectrum disorders
Authors: Abha R Gupta
Michelle Pirruccello
Feng Cheng
Hyo Jung Kang
Thomas V Fernandez
Jeremy M Baskin
Murim Choi
Li Liu
Adife Gulhan Ercan-Sencicek
John D Murdoch
Lambertus Klei
Benjamin M Neale
Daniel Franjic
Mark J Daly
Richard P Lifton
Pietro De Camilli
Hongyu Zhao
Nenad Šestan
Matthew W State
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2014
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/2040-2392-5-31

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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