Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism

Abstract

Molecular and neurobiological evidence for the involvement of neuroligins (particularly NLGN3 and NLGN4X genes) in autistic disorder is accumulating. However, previous mutation screening studies on these two genes have yielded controversial results. The present study explores, for the first time, the contribution of NLGN3 and NLGN4X genetic variants in Greek patients with autistic disorder. We analyzed the full exonic sequence of NLGN3 and NLGN4X genes in 40 patients strictly fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for autistic disorder. We identified nine nucleotide changes in NLGN4X--one probable causative mutation (p.K378R) previously reported by our research group, one novel variant (c.-206G>C), one nonvalidated single nucleotide polymorphism (SNP, rs111953947), and six known human SNPs reported in the SNP database--and one known human SNP in NLGN3 also reported in the SNP database. The variants identified are expected to be benign. However, they should be investigated in the context of variants in interacting cellular pathways to assess their contribution to the etiology of autism.

Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment

“…After the discovery of this mutation, the coding regions of NLGN3 were extensively sequenced afterwards (in almost 1,500 probands with ASD in total, see Table ). These studies screened cohorts of very different geographical origins but failed to identify promising nonsynonymous variant in NLGN3 (Talebizadeh et al, ; Avdjieva‐Tzavella et al, ; Blasi et al, ; Gauthier et al, ; Mikhailov et al, ; Pampanos et al, ; Steinberg et al, ; ; Vincent et al, ; Volaki et al, ; Wermter, Kamp‐Becker, Strauch, Schulte‐Körne, & Remschmidt, ; Xu et al, ; Yanagi et al, ; Ylisaukko‐oja et al, ). The screening of a Chinese cohort identified a novel missense variant Gly406Ser (Xu et al, ), but functional studies performed recently could not identify any functional consequences on NLGN3 function (Xu et al, ).…”

Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort

“…Considering that males have higher predisposition in ASD etiology, an involvement of the X-chromosome in autism susceptibility has been suggested by genetic and cytogenetic studies [9,10,11,12,13] and several putative candidate genes, including neuroligins, have been largely investigated [7,8,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Nonetheless, taking advantages of the new sequencing technologies, further insights might be provided in discovering new X-linked genetic variants associated with ASD predisposition or its etiology.…”

“…Deletion of exons 4, 5, and 6 in NLGN4X have been also found in autistic children, suggesting that alternative splicing variants might lead to abnormal neuroligin function in ASD [29,30]. Moreover, several noncoding genetic variants have been specifically found in ASD patients [31,32,33,34,35,36,37]. All these variations often segregate into ASD families [12,13] and can also be associated with different cognitive phenotypes, such as intellectual and language disabilities [32,37], highlighting the role of neuroligins in the ASD pathogenesis.…”

Biomarkers in Autism

“…Scattered findings related to NLGN4 and autism susceptibility occur across cultures. In the Chinese ASD cases, there were no significant findings regarding SNPs along NLGN4 gene and autism risk (23), yet in Greek ASD cases, nine nucleotide changes in NLGN4X are found to be associated with autism (24). …”