Balkan Journal of Medical Genetics

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
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DISCUSSION

The ASD is a neurodevelopmental disorder characterized by deficits in social communication and the presence of repetitive patterns of behavior, activity and interests [16]. The heritability of ASD is 90.0% and there is an increased recurrence risk in first-degree relatives of more than 20-fold [7,8]. The aim of this study was to better understand the role of the NRXN1 gene that is listed as one of the two strong candidate genes in SFARIGENE (an important database for autism) [12]. Neurexin proteins are the cell surface receptors that tie neuroligin (NLGN). The Ca2+-dependent neurexin/ neuro-ligin complex is present at synapses in the CNS is required for efficient neuro-transmission, and is involved in the formation of synaptic contacts. The NRXN1 is a gene that expresses NRXN1 (OMIM:600565) protein, located on chromosome 2 at position 2p16.3, has 22 exons, encodes 1477 amino acids, has 7505 bp. Small and large deletions in the NRXN1 gene, could play a role in the etiology of ASD. Additionally, missense and nonsense mutations in the NRXN1 gene could play a role in the pathogenesis of this disorder [17,18]. Mild/moderately and severely autistic patients were involved in our study. There were more male cases than female cases in the study parallel to the rates notified in the autism literature [3,10]. Two known mutations were described in two different cases. S14L (SFARIGENE Variant ID: GEN179R001) in patient P2 and L748I (SFARIGENE Variant ID: GEN179R007) in patient P9. S14L [17] and L748I [18] mutations have been described in patients with autism before. Both of these mutations were inherited from their father. The fathers of the children who carried the mutations were reevaluated psychiatrically and autismspectrum quotient (AQ) questionnaire [19,20], which has been used extensively to measure the broader autism phenotype (BAP), was applied to the fathers. The father of patient P2 did not have any psychiatric diagnosis and symptoms. His total AQ score was 22 (social skill: 6 points, attention switching: 3 points, attention to detail: 4 points, communication: 4 points, imagination: 5 points). This may indicate a reduced penetrance in the NRXN1 gene. Reduced penetrance in the NRXN1 gene has been reported before [18-21]. The father of patient P9 had attention deficit and hyperactivity disorder (ADHD) symptoms and mild obsessions. His total AQ score was 13 (social skill: 4 points, attention switching: 4 points, attention to detail: 3 points, communication: 1 points, imagination: 1 points). The ADHD and sub-threshold obsessive compulsive symptoms in one father (father of P9) was determined as remarkable. Genetic relatives of people with autism may show milder expression of characteristic traits for autism, referred to as the BAP [22]. Up to now, the S14L mutation has been detected in four subjects with ASD and not in 1201 controls [17]. The S14L mutation was described in two siblings in two families and the mutations in these two families were inherited from their father. In one of family, there was a boy who met the autism diagnostic interview-revised (ADI-R) criteria and his sister with central auditory processing problem, and decreased social interaction. Their father, who carried a heterozygous S14L mutation, had a learning disability. In the other family there was also a boy who met the ADI-R criteria and his brother had learning disability and hyperactivity [17]. The L748I mutation was previously identified in two families with ASD. There were four ASD patients in these two families; the L748I mutation was detected in three of four ASD patients, and also detected in one of two unaffected individuals. Because of that, this mutation was evaluated as an ASD susceptibility allele showing incomplete penetrance [18].

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