Alternative titles; symbols
DO: 0060243;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.2 | Stuttering, familial persistent, 1 | 184450 | Autosomal dominant | 3 | AP4E1 | 607244 |
A number sign (#) is used with this entry because of evidence that familial persistent stuttering-1 (STUT1) is caused by heterozygous mutation in the AP4E1 gene (607244) on chromosome 15q21.
Stuttering is a disorder of the flow of speech characterized by involuntary repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks (summary by Raza et al., 2010). Stuttering typically arises in young children, where it affects at least 15% of those in age range 4 to 6 years (Bloodstein, 1995). Stuttering usually resolves spontaneously before adolescence, leading to a population prevalence of 1 to 2% among adults. Stuttering beyond childhood is characterized by a significant bias towards males, with males outnumbering females by a ratio of 3:1 to 5:1 (Yairi et al., 1996).
Genetic Heterogeneity of Familial Persistent Stuttering
Also see STUT2 (609261), mapped to chromosome 12q24; STUT3 (614655), mapped to chromosome 3q; and STUT4 (614668) mapped to chromosome 16q.
Raza et al. (2013, 2015) reported a large family from Cameroon in which multiple members had persistent stuttering with onset around ages 2 to 5 years. Most reported that the stuttering was exacerbated under stress and that some improvement in fluency occurred with age. None of the affected individuals had any additional clinical signs or symptoms of other neurologic disease, particularly intellectual disability or spasticity.
The transmission pattern of STUT1 in the family reported by Raza et al. (2015) was consistent with autosomal dominant inheritance.
Inherited factors contributing to stuttering were demonstrated in studies by Howie (1981), Yairi et al. (1996), and Felsenfeld and Plomin (1997).
Chakravartti et al. (1979) studied an Indian kindred with 12 stammerers in 5 generations. Autosomal dominant inheritance was espoused. Stuttering is said to be unusually frequent in Japanese, low in Polynesians, and almost completely absent in American Indians.
Canhetti-Oliveira and Richieri-Costa (2006) presented 14 stuttering pedigrees. Five of the pedigrees had observed stutterers or recovered stutterers in 3 generations. A predominance of affected males was noted with an M:F ratio of 3.2.
As part of a linkage study to identify predisposing loci for stuttering, Drayna et al. (1999) assembled more than 100 small- to medium-sized unrelated families with multiple cases of persistent stuttering, chosen to represent the typical presentation of familial stuttering in the adult population. In these families, they observed a male-to-female ratio among the affected individuals that was strikingly different from the generally accepted ratio in the overall adult stuttering population. They found a male-to-female ratio of 1.57 as compared to 7.07 and 4.8 in 2 other studies.
Raza et al. (2015) mapped the STUT1 locus to chromosome 15q21 based on their identification of mutations in the AP4E1 gene (607244) in affected members of a family from Cameroon, West Africa, previously reported by Raza et al. (2013).
Raza et al. (2013) reported a large pedigree from the Republic of Cameroon in which at least 33 individuals had persistent stuttering. The large pedigree was divided into 5 subpedigrees, and these were subjected to genomewide linkage analysis individually or in groups. Evidence for linkage was found for several loci, including 2p, 3q, 3p, 14q, and 2 regions on 15q. On 2p, a peak lod score of 3.86 was found using markers rs11127193, D2S405, and rs7560152. On 3q, a peak lod score of 3.47 was found between rs711995 and D3S1311. On 3p, a peak lod score of 3.18 was found between markers rs304838 and D3S2432. On 14q, a peak lod score of 3.45 was found using rs975232, D14S588, rs8688, and rs987579. Results for 15q were not as strong, but these loci performed well in 2-locus analysis. A lod score of 3.42 was found by analyzing the data for the 2 loci on chromosome 15q, and lod scores ranging from 4.69 to 6.57 were obtained with a combined 2p/15q analysis. Raza et al. (2013) concluded that stuttering in this family is likely due to multiple alleles at different loci, which may have resulted from assortative mating. There was no evidence for a founder effect.
Heterogeneity
Shugart et al. (2004) performed a linkage study of stuttering using 392 markers distributed across the genome in 266 members of 68 families, including 188 affected individuals, in North America and Europe. The single largest pedigree in their sample gave an NPL score of 4.72 at D18S976. Other evidence for linkage was found at D18S78, with an NPL score of 5.143 and Z(lr) score of 2.63 (p = 0.0043). A second region of positive linkage scores was observed on proximal 18q, surrounding marker D18S847 (Z(lr) score, 2.47; p = 0.0068). Shugart et al. (2004) suggested that chromosome 18 may harbor a predisposing locus for stuttering, and that additional susceptibility loci for this disorder may exist.
In affected members of a large family of Cameroon descent (CAMST01) with STUT1, originally reported by Raza et al. (2013), Raza et al. (2015) identified heterozygosity for 2 missense variants in the AP4E1 gene that occurred in cis (V517I and E801K; 607244.0004). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. The same mutations on the same haplotype were subsequently found in 2 of 96 additional individuals from Cameroon with stuttering. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in slightly decreased assembly of the AP4 complex (about 80% of wildtype). Sequencing of the AP4E1 gene in unrelated affected individuals, including 93 from Cameroon, 132 from Pakistan, and 711 from North America, revealed 23 other rare variants in this gene, including small (1- to 3-bp) deletions, insertions, duplications, frameshifts, and stop codons; no truncating mutations were found in 558 ethnically matched control individuals. Investigation of large population databases, including the 1000 Genomes Project and Exome Sequencing Project, which are not phenotyped for speech fluency, found 3 loss-of-function AP4E1 variants among about 19,000 chromosomes, as well as several rare missense variants; all of these occurred at a significantly lower frequency compared to the variants observed in stuttering individuals. Studies in a yeast 2-hybrid system supported a direct interaction between the AP4 complex and NAGPA (607985), variations in which have also been implicated in stuttering (STUT2; 609261). The findings suggested that defects in intracellular trafficking play a role in persistent stuttering.
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Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering. Am. J. Hum. Genet. 97: 715-725, 2015. [PubMed: 26544806] [Full Text: https://doi.org/10.1016/j.ajhg.2015.10.007]
Raza, M. H., Riazuddin, S., Drayna, D. Identification of an autosomal recessive stuttering locus on chromosome 3q13.2-3q13.33. Hum. Genet. 128: 461-463, 2010. [PubMed: 20706738] [Full Text: https://doi.org/10.1007/s00439-010-0871-y]
Shugart, Y. Y., Mundorff, J., Kilshaw, J., Doheny, K., Doan, B., Wanyee, J., Green, E. D., Drayna, D. Results of a genome-wide linkage scan for stuttering. Am. J. Med. Genet. 124A: 133-135, 2004. [PubMed: 14699610] [Full Text: https://doi.org/10.1002/ajmg.a.20347]
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