Investigation of the potential impact of CNTNAP2 and SETBP1 variants on developmental language disorder

Objective: Developmental Language Disorder (DLD) is the most common developmental disability that hinders children's ability to communicate. It is characterized by a disruption in normal language development that cannot be explained by factors such as hearing loss, neurological/psychiatric disorders, or environmental deprivation. In addition to environmental factors, strong genetic factors are known to be involved in the pathomechanism of DLD. This study aimed to determine the role of sequence variations in the SETBP1 and CNTNAP2 genes, as well as the suspected environmental variables, in the etiology of DLD. Methods: Between September 2022 and March 2023, thirty children aged 2-7 years who presented to the Pediatric Psychiatry Clinics of the Necmettin Erbakan University Faculty of Medicine (NEUFM) and were diagnosed with language disorders according to DSM-V criteria, and whose developmental levels were assessed using the AGTE, were examined for genetic and environmental factors that could be responsible for etiology. Thirty healthy children with no underlying diseases, matched for age and gender with the case group, who presented to the Medical Genetics Clinics of NEUFM, were included as a control group. DNA samples isolated from peripheral blood of both groups were analyzed for SETBP1 and CNTNAP2 genes (custom design panel) using next-generation sequencing. The clinical significance of the identified variants was evaluated, and variant verification and segregation analyses were performed by Sanger sequencing. The obtained data were compared using appropriate statistical methods. Results: The most common type of variant was deep intronic in the CNTNAP2 gene (75%), and missense variants in the SETBP1 gene (60%). 29 SNVs were observed in both case and control groups, whereas three SNVs (rs186624619, rs17170742, rs373599564) and two variants of unknown significance (CNTNAP2: c.973C>G:p.P325A and CNTNAP2: c.2236G>A:p.D746N) were observed only in the case group. One of the rare variants was novel, and in silico analyses of both yielded conflicting results. The segregation study showed that they were paternally inherited from unaffected parents. The frequencies of polymorphisms were compared between the case and control groups. The SETBP1 rs11082414-CC genotype frequency was significantly higher in patients compared to the controls. (p=0.024). Among non-genetic factors, the case group had a higher average birth weight (p=0.043), and a lower average lactation duration (p=0.044). Conclusion: The family history, male gender, lactation duration of less than 15 months, and the SETBP1 rs11082414-CC variant may be risk factors for DLD. Identifying risk factors can help create preventive and treatment strategies for high-risk families.