Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.

Abstract

Purpose: Prior studies investigating the genetic architecture of pediatric motor speech disorders (MSDs) have been limited by small sample sizes and an exclusive focus on apraxia. We aimed to identify pathogenic genomic variants associated with MSDs in a large pediatric population referred for exome sequencing (ES).

Methods: We identified pediatric patients with MSDs who had clinical ES between 2012-2022. The rate of pathogenic/likely pathogenic (P/LP) findings considered causative of the MSD phenotype was determined and delineated by sex and neurodevelopmental comorbidity. Gene-based burden testing compared the rate of P/LP variants in each gene in MSD cases vs. a comparison clinical ES cohort.

Results: Positive diagnostic results were detected in 527 of 2004 (26.3%) patients with MSDs, with higher diagnostic rates for females and for individuals with neurodevelopmental comorbidities. P/LP sequence variants were detected in 262 genes. Gene-based, case-referent burden analysis revealed that 30 genes were nominally associated with MSDs, two of which (SETBP1, ADCY5) survived exome-wide correction.

Conclusion: Over 25% of patients with MSDs were found to harbor P/LP variants in 262 genes, many of which have not previously been associated with MSDs. Potential clinical implications include early implementation of intensive speech therapy for children diagnosed with monogenic causes of MSDs.