Stuttering Panel

Stuttering (also called stammering) is speech characterized by frequent repetition; 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 of around 30 months of age (Yairi and Ambrose. 1992. PubMed ID: 1405533). Stuttering often resolves spontaneously before adulthood, particularly in females. In rare cases, stuttering can occur in adulthood as a result of brain injury (Fawcett. 2005. PubMed ID: 15685118) or drug use (Krishnakanth et al. 2008. PubMed ID: 18787667). Secondary behaviors, such as eye blinking or other involuntary head movements, are not uncommon (Prasse and Kikano. 2008. PubMed ID: 18540491).

The advantages of genetic testing may primarily be limited to aiding in the prediction of speech therapy outcomes in the context of persistent developmental stuttering (Frigerio-Domingues et al. 2019. PubMed ID: 31003007). Patients and their families may also benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

Variants in GNPTAB, GNPTG, NAGPA, and AP4E1 have been associated with stuttering (Kang et al. 2010. PubMed ID: 20147709; Raza et al. 2015. PubMed ID: 26544806). Nearly all variants were missense and the great majority of the patients were heterozygous for the variants, although a few homozygous individuals in consanguineous kindreds were also reported. Penetrance of the variants for non-syndromic stuttering does not appear to be complete. The contribution of de novo variants in the GNPTAB, GNPTG, NAGPA, and AP4E1 genes to the development is stuttering is not known.

GNPTAB and GNPTG variants have also been reported in patients with mucolipidosis types II and III. In contrast to stuttering, mucolipidosis appears to be a solely autosomal recessive disorder associated with different, more severe variants (Raza et al. 2016. PubMed ID: 26130485). AP4E1 variants have also been reported in patients with autosomal recessive syndromic intellectual disability due to AP4E1 deficiency (Moreno-De-Luca et al. 2011. PubMed ID: 20972249; Abou Jamra et al. 2011. PubMed ID: 21620353; Kong et al. 2013. PubMed ID: 23472171). However, patients with persistent stuttering that are heterozygous for AP4E1 variants do not appear to display any features consistent with the autosomal recessive phenotype (Raza et al. 2015. PubMed ID: 26544806).

Copy number variants spanning one or more exons have been reported in association with GNPTAB, NAGPA and AP4E1-related disorders. A heterozygous deletion encompassing the entire NAGPA gene has been reported in a patient with intellectual disability, speech problems, spastic movement disorder, and tall stature (Asadollahi et al. 2014. PubMed ID: 25106414). A homozygous deletion encompassing the entire AP4E1 gene has been reported in patients with spastic cerebral palsy (Moreno-De-Luca et al. 2011. PubMed ID: 20972249; Gambin et al. 2017. PubMed ID: 27980096). Large deletions, duplications, and insertions involving one or more exons of GNPTAB have been reported in patients with mucolipidosis (Tappino et al. 2008. PubMed ID: 17964840; Otomo et al. 2009. PubMed ID: 19197337; Velho et al. 2019. PubMed ID: 30882951). For GNPTAB, GNPTG, NAGPA, and AP4E1, the contribution of gross deletions, duplications, and/or insertions to stuttering is not clear at this time.

The GNPTAB, GNPTG, and NAGPA genes encode enzymes involved in the lysosomal enzyme-targeting pathway. The AP4E1 gene encodes a protein involved in protein-sorting at the trans-Golgi network that physically interacts with the NAGPA enzyme.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Approximately 8-16% of patients with persistent stuttering have variants in GNPTAB, GNPTG, and NAGPA (Raza et al. 2016. PubMed ID: 26130485). Variants in AP4E1 may underlie an additional ~2-4% of cases of persistent stuttering (Raza et al. 2015. PubMed ID: 26544806).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).