AI Article Synopsis

  • Developmental stuttering is a complex speech disorder with a low genetic explanation rate; previous gene research has only accounted for about 2.1% - 3.7% of chronic cases, primarily focusing on certain lysosomal and signaling genes.* -
  • This study aimed to identify new genetic factors linked to stuttering in a large family, using exome sequencing, which revealed a novel variant in the NAGPA gene and others in different genes associated with severe stuttering.* -
  • The findings suggest that genetic diversity may influence stuttering, especially highlighting potential links between dopamine signaling and the disorder, indicating the need for further screening in larger populations.*

Article Abstract

Background: Developmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in GNPTAB, GNPTG, and NAGPA involved in lysosomal pathway and AP4E1, IFNAR1, and ARMC3-signaling genes reported till date explain only ∼2.1% - 3.7% of persistent stuttering cases.

Aim: We aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (n = 27) and further validation on additional extended family members (n = 21).

Materials & Methods: We employed hypothesis-free and pathway-based analyses.

Results: A novel heterozygous exonic variant NM_016256.4:c.322G > A in NAGPA with reduced penetrance and predicted pathogenicity segregated with the phenotype in a large subset of the family. Reanalysis to identify additional disease-causing variant(s) revealed exonic heterozygous variants each in RIMS2 and XYLT1 in severely affected members; and IGF2R variant in a small subset of the family. Furthermore, pathway-based analysis uncovered NM_022089.4:c.3529G > A in ATP13A2 (PARK9) in affected members; and variants in GNPTAB and GNPTG of minor significance in a few affected members.

Discussion: Genotype-phenotype correlation efforts suggest that the combined effect of gene variants at multiple loci or variants in a single gene in different subsets of the pedigree (genetic heterogeneity) may be contributing to stuttering in this family. More importantly, variants identified in ATP13A2, a Parkinson's disease gene also implicated in lysosomal dysfunction, and RIMS2 suggests for the first time a likely role of dopamine signaling in stuttering.

Conclusion: Screening for these variants in independent stuttering cohorts would be astute.

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Source
http://dx.doi.org/10.1111/ahg.12579DOI Listing

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