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Abstract
BackgroundSynaptic genes, NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs. But no such rare variant in these two genes has as yet been adequately replicated in Chinese population and no common variant has been further investigated to be associated with ASDs.Methods7 known ASDs-related rare variants in NLGN3 and NLGN4X genes were screened for replication of the initial findings and 12 intronic tagging single nucleotide polymorphisms (SNPs) were genotyped for case-control association analysis in a total of 229 ASDs cases and 184 control individuals in a Chinese Han cohort, using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry.ResultsWe found that a common intronic variant, SNP rs4844285 in NLGN3 gene, and a specific 3-marker haplotype XA-XG-XT (rs11795613-rs4844285-rs4844286) containing this individual SNP were associated with ASDs and showed a male bias, even after correction for multiple testing (SNP allele: P = 0.048, haplotype:P = 0.032). Simultaneously, none of these 7 known rare mutation of NLGN3 and NLGN4X genes was identified, neither in our patients with ASDs nor controls, giving further evidence that these known rare variants might be not enriched in Chinese Han cohort.ConclusionThe present study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population, and further supports the hypothesis that defect of synapse might involvement in the pathophysiology of ASDs.
Highlights
Synaptic genes, neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X), two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs
10-20% of ASDs cases are already identified to be attributable to genetic syndromes with highly penetrant chromosomal abnormalities, known rare mutations, and copy number variants (CNVs) [1], but the causes of the majority of ASDs cases remain further determined and the biological basis remains pooly understood
Neuroscience research efforts have focused on elucidating the neurobiological basis of ASDs, and a growing body of evidence indicates that ASDs are brain development disorders occuring during prenatal and postnatal period, and to put forward the possibility that the neuropathology of ASDs may present an on-going process extending through early childhood and into adulthood [6,7]
Summary
NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs. Considering the fact that the normal functions of brain depend on proper working of the diverse synaptic components distributed in various compartments of the synapse, which is specialized site of cell-cell contact allowing communication between neurons, the synaptic hypothesis was proposed that abnormalities at the synapse may contribute to development of brain disorders such as ASDs and mental retardation. A genetics topic in ASDs has emerged focusing on identification of the synaptic genes contributing to the formation and function of the synapse. The synaptic hypothesis was confirmed by the discovery of mutations in trans-synaptic adhesion proteins, such as neuroligins and neurexins, in a small fraction of individuals with ASDs, which was proposed to alter synaptic homeostasis and/or impair synapse development [8,9]
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