Mucolipidosis and Stuttering via the GNPTG Gene

Mucolipidosis III gamma (ML III γ) (OMIM 252605), also called pseudo-Hurler polydystrophy, is part of the lysosomal storage disease family. The disease manifests clinically in childhood. Phenotypic characteristics include moderate dysostosis multiplex, joint stiffness (in the shoulders, hips, and fingers), coarsening of facial features, genu valgum, restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left ventricular hypertrophy, and in a few cases, mild cognitive impairment (Raas-Rothschild and Spiegel GeneReviews 2012, www.genereviews.org). ML III γ is distinguished from Mucolipidosis III alpha/beta (ML III α/β) by a milder phenotype and by the underling causative variants.

Stuttering (also called stammering) is speech that is 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 (Prasee and Kikano. Am Fam Physician 77:1271-1276, 2008).

ML III γ is inherited in an autosomal recessive manner and is caused by variants in GNPTG (encoding the protein N-acetylglucosamine-1-phosphotransferase subunit gamma) (Raas-Rothschild et al. J Clin Invest 105:673-681, 2000). Missense, nonsense, and frameshift variants as well as small intragenic insertions and deletions have been reported as disease causing (eg Persichetti et al. Hum Mutat 30:978-84, 2009).

Variants in GNPTG, located on chromosome 16, have been associated with stuttering (Kang et al. N Engl J Med 362:677-685, 2010). GNPTG encodes the γ subunit of GlcNAc-phosphotransferase, a protein involved in the lysosomal enzyme-targeting pathway. Three heterozygous GNPTG variants were reported in stuttering patients: two missense and one in-frame duplication of three amino acids. Penetrance of the variants does not appear to be complete. Variants in the GNPTAB and NAGPA genes, also involved in the lysosomal enzyme-targeting pathway, were similarly reported in stuttering patients. PreventionGenetics offers testing of all three genes.

The sensitivity for the GNPTG sequencing test is >95% for ML III γ.Kang et al. 2010 reported that 25 of 393 stuttering patients (6%) had variants in one of the three genes (GNPTAB, GNPTG, and NAGPA). Four of the 25 patients had variants in GNPTG.

This test provides full coverage of all coding exons of the GNPTG gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.