Homozygous mutations in GNPTAB and GNPTG are classically associated with mucolipidosis II (ML II) alpha/beta and mucolipidosis III (ML III) alpha/beta/gamma, which are rare lysosomal storage disorders characterized by multiple pathologies. Recently, variants in GNPTAB, GNPTG, and the functionally related NAGPA gene have been associated with non-syndromic persistent stuttering. In a worldwide sample of 1013 unrelated individuals with non-syndromic persistent stuttering we found 164 individuals who carried a rare non-synonymous coding variant in one of these three genes. We compared the frequency of these variants with those in population-matched controls and genomic databases, and their location with those reported in mucolipidosis. Stuttering subjects displayed an excess of non-synonymous coding variants compared to controls and individuals in the 1000 Genomes and Exome Sequencing Project databases. We identified a total of 81 different variants in our stuttering cases. Virtually all of these were missense substitutions, only one of which has been previously reported in mucolipidosis, a disease frequently associated with complete loss-of-function mutations. We hypothesize that rare non-synonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent stuttering cases, and that variants in GNPTAB and GNPTG are at different sites and may in general, cause less severe effects on protein function than those in ML II alpha/beta and ML III alpha/beta/gamma.

Stuttering is a common disorder that affects the flow of speech and is characterised by uncontrollable repetitions, prolongations or interruptions in speech. The aetiology of developmental stuttering is still not well understood, however genetic studies over the past decade have made some important advances. Strong evidence for genetic factors in this disorder comes from twin and adoption studies, as well as from family studies that include measures of familial aggregation, segregation and genetic linkage analyses. However, Mendelian segregation of the disorder in families does not occur, and thus stuttering is a complex genetic disorder which poses a challenge for linkage and other genetic analyses. Nevertheless, genetic linkage studies have defined numerous loci‐carrying genes that can cause persistent stuttering, and several causative genes have recently been identified. Application of massively parallel DNA (deoxyribonucleic acid) sequencing holds the promise of facilitating the identification of genes that cause stuttering and other speech and language disorders. Key Concepts Stuttering is a disorder of the flow of speech, in which the affected individuals know what they wish to say but are unable to say it owing to uncontrollable repetitions, prolongations or interruptions in their speech. Developmental stuttering typically arises at a characteristic time during the acquisition of speech in children, and approximately 75–80% children recover, sometimes with and sometimes without the aid of speech therapy. Twin studies provide strong evidence for the involvement of genetic factors in developmental stuttering. Stuttering is a complex genetic disorder in which Mendelian segregation does not occur. Genetic linkage studies in families have defined numerous loci for persistent stuttering, and several causative genes have recently been identified.