Genetic Traces in Autism Spectrum Disorders: A Whole Exome Sequencing Study from Türkiye

Autism spectrum disorders (ASDs) are defined as a large spectrum of phenotypes whose basic definition is deficiency in social interactions, particularly during pediatric stages. Through clinical evaluations, it would be challenging to diagnose since the symptoms may be disregarded or controversial. Hence, molecular approaches could be powerful for differential and certain diagnosis. Moreover, considering the possible genetic complexity of the disease, the rates of molecular diagnosis remain insufficient. Nevertheless, the number of newly identified ASD-monogenic inheritance relationships is escalating daily. This underscores the increasing importance of comprehensive molecular tests, such as whole exome sequencing (WES), which encompass all relevant genes. Furthermore, reporting population-specific variants is critical to validate already listed ones and decipher novel ones. In the present study, we aimed to document the disease-related variants in Turkish patients with ASD.

This study evaluated the WES outcomes of 75 ASD patients with normal results in Fragile X testing, cytogenetic analysis, and molecular karyotyping. All patients were diagnosed with ASD based on the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).

The average age of the participants was 8.2 (±5.0) years. A higher percentage of the participants was male (73.3%) compared with female (26.7%). Eighteen patients (24%) had pathogenic or likely pathogenic (LP) variants, while 34 (45.3%) exhibited variants of unknown significance (VUS). In 30.7% of the cases, no clinically relevant variants were found. The MECP2 gene was most frequently affected, followed by EP300 and PTEN. Additionally, four patients carried novel de novo missense variants in the KMT2C, MECP2, PTEN, and TRRAP genes.

Genetic diagnosis of ASD would be useful for confirming the underlying etiologies, devising personalized therapeutic strategies, and offering family counseling. Although WES has been employed in ASD patients for an extended period, the identification of gene and variant spectra across diverse cohorts and the discovery of novel variants continues to hold significant scientific importance.