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Mol Autism DOI:10.1186/2040-2392-5-31

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Publication TypeJournal Article
Year of Publication2014
AuthorsGupta, AR, Pirruccello, M, Cheng, F, Kang, HJung, Fernandez, TV, Baskin, JM, Choi, M, Liu, L, Ercan-Sencicek, AGulhan, Murdoch, JD, Klei, L, Neale, BM, Franjic, D, Daly, MJ, Lifton, RP, De Camilli, P, Zhao, H, Sestan, N, State, MW
JournalMol Autism
Date Published2014

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 

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.


Alternate JournalMol Autism
PubMed ID24860643
PubMed Central IDPMC4032628
Grant ListK08 MH099424 / MH / NIMH NIH HHS / United States
R25 MH077823 / MH / NIMH NIH HHS / United States
R37 NS036251 / NS / NINDS NIH HHS / United States