NAGPA – Stutter Disorder

NAGPA has emerged as an important candidate gene in the etiology of stutter disorder. Multiple lines of evidence from case reports and multi‐patient studies have consistently implicated NAGPA in the pathogenesis of speech dysfluency. Studies have documented several variant classes including missense and loss‑of‑function changes across unrelated probands (PMID:36618124). In one study of 64 probands (PMID:36618124), recurrent variants in NAGPA were observed, supporting the gene‐disease association.

Genetic evidence further shows that mutations such as c.252C>G (p.His84Gln) are reported in affected individuals. Although explicit segregation counts in families were not uniformly reported, the recurrence of these mutations across independent cohorts strengthens the genetic link. This is complemented by additional case series that reinforce the consistency of variant detection in NAGPA among stutter disorder probands (PMID:21663442).

Functional studies provide key mechanistic insights by demonstrating that NAGPA mutations impair protein folding and reduce enzymatic activity, which is critical for proper lysosomal targeting. Biochemical assays have shown that such mutations lead to reduced GlcNAc-1-phosphodiester-N-acetylglucosaminidase activity, a finding that directly correlates with the stuttering phenotype (PMID:21956109).

Moreover, integrated analyses reveal that the combination of genetic recurrence and concordant in vitro functional deficits builds a strong case for NAGPA’s role in stutter disorder. While additional evidence exists that exceeds standard ClinGen scoring thresholds, the current cumulative data justify a strong clinical validity classification.

This synthesis supports diagnostic decision‑making and highlights the utility of genetic testing for NAGPA in stutter disorder. The demonstrated molecular dysfunction offers a promising target for potential therapeutic interventions and further research.

Key Take‑Home: NAGPA mutations are strongly associated with stutter disorder, and their identification in probands can significantly inform clinical evaluations as well as future research into targeted therapies.

References

• Annual review of genomics and human genetics • 2011 • Genetics of speech and language disorders PMID:21663442
• Advanced genetics (Hoboken, N.J.) • 2021 • Evaluation of recurrent GNPTAB, GNPTG, and NAGPA variants associated with stuttering PMID:36618124
• The Journal of biological chemistry • 2011 • Analysis of mannose 6-phosphate uncovering enzyme mutations associated with persistent stuttering PMID:21956109
• Molecular genetics and metabolism • 2012 • A role for inherited metabolic deficits in persistent developmental stuttering PMID:22884963
• Neurobiology of disease • 2014 • A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering PMID:24807205

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