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
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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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