Stuttering via the NAGPA Gene

Stuttering (also called stammering) is speech characterized by frequent repetition or prolongation of sounds, syllables, or words or by frequent hesitations or pauses that disrupt the rhythmic flow of speech. Stuttering affects ~1% of the population and has a mean onset around 30 months of age (Yairi et al. J Speech Hear Res 35:782-788, 1992). Stuttering often resolves spontaneously before adulthood, particularly in females. In rare cases, stuttering can occur in adulthood as a result of brain injury (Fawcett. CNS Spectrums 10:94-95, 2005) or drug use (Krishnakanth et al. Prim Care Companion J Clin Psychiatry 10:333-334, 2008). Secondary behaviors, such as eye blinking or other involuntary head movements, are not uncommon (Prasse and Kikano. Am Fam Physician 77:1271-1276, 2008).

Variants in the gene NAGPA have been associated with stuttering (Kang et al. N Engl J Med 362:677-685, 2010). NAGPA encodes N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (commonly known as the “uncovering enzyme”), a protein involved in the lysosomal enzyme-targeting pathway. Two missense and one frameshift variant near the 3’ end of the gene were reported. Affected individuals were heterozygous or homozygous for the variants. Penetrance of the variants does not appear to be complete. Variants in the GNPTAB and GNPTG genes, also involved in the lysosomal enzyme-targeting pathway, were similarly reported in stuttering patients. PreventionGenetics offers testing of all three genes.

Kang et al. 2010 reported that 25 of 393 patients (6 %) had variants in one of three genes (GNPTAB, GNPTG, and NAGPA). About one third of the 25 patients had variants in NAGPA.

This test provides full coverage of all coding exons of the NAGPA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).