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Neuroanatomical differences associated with lysosomal variants in children who stutter (CWS)
Poster Session D, Thursday, October 1, 4:30 - 6:30 pm, Wangari Maathai
This poster is part of the Sandbox Series.
Yookyung Kim1, Ho Ming Chow2, Margit Burmeister1, Jim Delproposto1, Soo-Eun Chang; 1University of Michigan, 2University of Delaware
MOTIVATION. Stuttering is a highly heritable neurodevelopmental disorder that impedes speech fluency and negatively impacts quality of life. Despite a high lifetime incidence of 5-8%, its underlying biological mechanisms remain poorly understood. Previous neuroimaging studies, consistent with the GODIVA model, have identified both structural and functional differences within the basal ganglia-thalamocortical (BGTC) circuit that underlie deficits in speech timing and sensorimotor integration. However, the genetic associations of these neural differences are not fully characterized. To date, family-based linkage and sequencing studies have identified rare variants in lysosomal enzyme trafficking genes (GNPTAB, GNPTG, NAGPA, and AP4E1) that segregate within families affected by stuttering, yet whether and how these variants influence brain structure and function has not been investigated in humans. This study integrates genomic and multimodal neuroimaging data to characterize the neurobiological correlates of these genetic variants and establish a gene-brain relationship for developmental stuttering. STUDY DESIGN. Seventy-one children who stutter (CWS; ages 3-15) and age-matched fluent controls were enrolled as part of an ongoing longitudinal study. Participants completed a comprehensive battery assessing cognitive ability (WASI, TONI-4), speech-language proficiency (e.g., GFTA-2, TACL, EVT), and stuttering severity (SSI-4). T1-weighted structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rsfMRI) were acquired on a GE 3T Signa HDx scanner with an 8-channel head coil. Genomic DNA was extracted from saliva and analyzed using whole-exome sequencing (WES). Sequence data underwent quality control, alignment to the GRCh38 reference genome, variant calling, and annotation. Post-calling variants were processed to generate cross-sample summaries and prioritize variants in targeted stuttering-associated and neurodevelopmental genes based on minor allele frequency (MAF) thresholds (less than 0.05) and predicted variant consequences. Identified variants are being verified via Sanger sequencing. Neuroimaging analyses focus on BGTC regions of interest, including bilateral putamen, caudate nucleus, thalamus, supplementary motor area (SMA), pre-SMA, and inferior frontal gyrus (IFG). Outcome measures include gray matter volume via voxel-based morphology (VBM), white matter microstructural properties reflected by fractional anisotropy (FA) from DTI, and functional connectivity from rsfMRI. General linear models (GLMs) will test association between variant carrier status and neuroimaging measures across three groups: CWS carriers, CWS non-carriers, and fluent controls, controlling for age and sex. Group differences in stuttering severity and behavioral measures will also be evaluated. PRELIMINARY RESULTS. Filtering yielded approximately 280 variants across the targeted gene set. Among these filtered variants, 12 were identified in four candidate genes: GNPTAB (6 variants), NAGPA (3 variants), AP4E1 (2 variants), and GNPTG (1 variant) across 15 CWS (9 females, 6 males). Most were missense single-nucleotide variants (SNVs). Notably, a high-impact NAGPA deletion (chr16:5028366 CTG to CG) was identified in siblings, supporting familial co-segregation. EXPECTED OUTCOMES. We hypothesize that CWS carrying potentially deleterious lysosomal variants will exhibit significant neuroanatomical differences within the BGTC circuit, specifically atypical gray matter volume, altered white matter integrity, and distinct functional connectivity, compared to non-carrier CWS and fluent controls. These findings will provide the neural basis of lysosomal pathway disruption in developmental stuttering.
Topic Areas: Disorders: Developmental, Genetics