MUTATION ANALYSIS OF THE NRXN1 GENE IN AUTISM SPECTRUM DISORDERS
Onay H1, Kacamak D, Kavasoglu AN, Akgun B, Yalcinli M, Kose S, Ozbaran B
*Corresponding Author: Huseyin Onay, M.D., Ph.D., Department of Medical Genetics, Ege University School of Medicine, Bornova, Izmir, Turkey. Tel: +90-232-3903961. Fax: +90-232-3903971. E-mail: onayhuseyin@ gmail.com; huseyin.onay@ege.edu.tr
page: 17

INTRODUCTION

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by persistent impairment in reciprocal social communication and social interaction, and restricted, repetitive patterns of behavior, interests, or activities, and with increasing prevalence in recent years [1]. Prevalence ratio of ASD was stated to be in the range of 0.6 to 2.64% [2-3]. A male predominance was observed and male-to-female ratio was 5 [4]. There is no accurate etiological factor that causes ASD; however ASD is likely to result from a complex interaction between genetic and environmental factors [3-5]. Autism spectrum disorder is one of the most heritable psychiatric disorders and heritability of ASD is 90.0% [6]. There is an increased recurrence risk of more than 20-fold in first-degree relatives [7]. Comprehensive genetic testing of children with ASD revealed a chromosomal or mendelian cause in 15.0-40.0% of the patients [8]. Classifying autism into ‘essential’ and ‘complex’ subgroups may be beneficial to understanding the genetic basis of the disorder [9]. Essential autism is usually present in about 75.0% of cases and is characterized by absence of dysmorphic features and comorbidities. In this group, there is a higher male-to-female ratio and higher sibling recurrence risk compared to the complex autism. In complex or syndromic autism, some dysmorphic features and neurological and medical symptoms such as seizures accompany autism. Because of the comorbidities, prognosis is worse in this group. The distinction between the two types of autism is important because prognosis, recurrence risk and genetic approach are different between the two groups [10]. Understanding the genetic basis of autism is challenging. The genetics of autism is an active research area and up to now, nearly all kinds of study designs have been used including family based, case-control, genome wide association studies (GWAS) and next generation sequencing (NGS). All these genetic studies reported that more than 600 genes and 2000 loci have been related to ASD and 83.4% of the detected variants are rare variants [11]. Genetic variations detected in ASD can be classified into three subgroups: in up to 5.0% of the cases, cytogenetic anomalies can be detected with standard karyotyping, and an additional 3.0-5.0% have been found using fluorescence in situ hybridization (FISH); in 10.0-35.0% of cases, copy number variants (CNVs) can be found with microarray analysis and in 5.0% of the cases, single gene mutations might be found [10]. In the complex/syndromic autism group, it is relatively easier to find the genetic etiology with the help of dysmorphic features. Fragile X syndrome, Angelman syndrome or Rett syndrome are examples of syndromic ASD. Approximately 1.0-3.0% of children with ASD have been found to have fragile X syndrome. A considerable number of children being evaluated for autism FMR1 premutations (55-200 CGG repeats) have also been found [10]. In the essential autism group, many genes have been blamed, and the likelihood of identifying a single gene mutation in an essential autism patient is extremely low. SFARIGENE [11] (https://gene.sfari.org) is a web-based database of candidate genes associated with ASD and all the genes annotated in this database are grouped in seven categories according to their relevance to ASD. A number of these genes are becoming clinically relevant. Especially the genes associated with the synaptic cell adhesion and synaptic function, such as neurexin 1 (NRXN1), neuroligin 3 (NLGN3), neuroligin 4 (NLGN4) and SHANK3 have attracted great attention. Neurexins function in the vertebrate nervous system as cell adhesion molecules and receptors. Neuroxin 1 is a cell surface receptor that binds neuroligins to form a calcium-dependent neurexin/neuroligin complex at synapses in the central nervous system (CNS). This complex is important for efficient neuro transmission and is involved in the formation of synaptic contacts [12]. The NRXN1 gene is listed as a strong candidate gene in the SFARIGENE database and heterozygous deletions, and up to now, point mutations have been detected in the NRXN1 gene in a limited number of patients with ASD [11]. Herein, in order to investigate the prevalence of NRXN1 mutations in ASD patients, sequencing of the NRXN1 gene was performed in 30 essential ASD patients with a normal karyotype and negative FMR1 analysis for fragile X syndrome.



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