Abstract
Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10−6 for the European controls; odds ratio = 2.42, p-value = 6.33 × 10−3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence.
Highlights
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an early onset, typically prior to age 3, characterized by impaired social interactions, absent or limited verbal communication, and stereotyped and restricted pattern of interests [1]
We performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting
We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence
Summary
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an early onset, typically prior to age 3, characterized by impaired social interactions, absent or limited verbal communication, and stereotyped and restricted pattern of interests [1]. Considering the higher occurrence of ASD in males than in females, with a ratio of roughly 4:1, a role for the X-chromosome in the ASD etiology has been suggested [7,9] In this regard, cytogenetic abnormalities highlight the putative involvement of the loci from Xq12 to Xq21 and Xp22 in autism pathogenesis [10,11], as well as associations with structural variants that have been reported for some X-chromosomal genes, such as NLGN4X and MECP2 genes [12,13,14,15]. The involvement of neuroligins in ASD has been firstly confirmed in two Swedish families by a de novo missense mutation (R451C) in NLGN3 and a frameshift mutation (1186insT) in NLGN4X causing premature protein termination (D396X), respectively associated with typical autism and Asperger’s syndrome [12] Both these mutations resulted in an intracellular retention of the mutant proteins, with a consistent loss of the synaptic activity, leading to neurodevelopmental defects and mental retardation [22,23]. Three haplotype sets in NLGN4X (rs3810686(T), rs1882260(C)), (rs6638575(G), rs3810686(T), rs18882260(T)) and (rs6638575(A), rs3810686(C), rs18882260(C)), have been positively associated with nonspecific mental retardation (Intelligence Quotients IQs < 70) and social disability scores ≤ 8 [36] and genetic variants in NLGN4X have a significant effect on male cognitive abilities, highlighting the role of neuroligins in psychiatric conditions [37]
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