De novo protein-coding gene variants in developmental stuttering.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Speech Pathology

Background:

• Developmental stuttering is a common childhood speech disorder with transient or persistent forms.
• Previous research identified six genes associated with persistent stuttering, suggesting a monogenic basis.
• The genetic underpinnings of stuttering, especially its heterogeneity, remain incompletely understood.

Purpose of the Study:

• To identify novel genetic variants associated with stuttering using a de novo variant screening approach.
• To investigate potential overlaps in brain-related processes among genes implicated in monogenic stuttering.
• To explore the relationship between stuttering and other neurodevelopmental disorders.

Main Methods:

• Exome sequencing of 85 parent-child trios with stuttering.
• Bioinformatic analyses of gene-expression and brain structural connectivity data.
• Identification and validation of pathogenic and likely pathogenic variants in candidate genes.

Main Results:

• Identified pathogenic variants in SPTBN1 and likely pathogenic variants in PRPF8, TRIO, ZBTB7A, FLT3, and IREB2.
• Found a direct genetic link between stuttering and neurodevelopmental disorders like speech delay and aphasia.
• Demonstrated heterogeneity in biological pathways associated with monogenic stuttering genes, indicating diverse etiological bases.

Conclusions:

• This study provides the first direct genetic evidence linking stuttering to other neurodevelopmental disorders.
• The findings highlight the genetic heterogeneity underlying monogenic forms of stuttering.
• New genes implicated in stuttering offer insights into speech development and related disorders.