Evaluation of recurrent GNPTAB, GNPTG, and NAGPA variants associated with stuttering

Chandru, Jayasankaran; Jeffrey, Justin Margret; Krishnamoorthy, Mathuravalli; Srisailapathy, C. R. Srikumari

doi:10.1002/ggn2.10043

Cited by 5 publications

(5 citation statements)

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“…Congenital factors play a role in some people who stutter. In past studies, researchers estimated that alteration of three genes GNPTAB, GNPTG, and NAGPA, were present in 9% of those who have a family history of stuttering (Gunasekaran et al, 2021). It is not yet clearly known whether the differences in brain structures of stutterers is the consequence or the cause, but recent research on older children confirms structural differences that don't appear in younger children, thereby giving strength to the argument that at least some of the differences are not a consequence of stuttering (Watkins et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

The Difference between Monolingual and Bilingual Stutterers: A Systematic Review

Qi¹

2023

IJPS

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The article is a comprehensive review regarding group differences of brain structures, cognitive process, and emotional responses between monolingual people who stutter (MWS) and bilingual people who stutter (BWS). Until now, researchers have been examining MWS and BWS separately, yet the compare between these two groups of people is lacking. In this work, the overview of MWS and BWS are introduced, different types and traits of stutter between MWS and BWS are compared, and the differences between brain structure, executive force, motor control, and cognitive reserve are investigated and synthesized based on previous studies. Both MWS and BWS have executive deficits in speech motor control, while BWS seem to be classified as having greater potential in language inhibitory and switching, thus transferring to general executive control. The conclusions are that BWS generally experience increased neural connectivity due to larger volume of grey and white matter than MWS, and thus gaining cognitive control abilities. Further research is warranted for the bilingual advantage and the exact etiology for stuttering.

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Section: Methodsmentioning

confidence: 99%

The Difference between Monolingual and Bilingual Stutterers: A Systematic Review

Qi¹

2023

IJPS

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“…Вплив раси, етнічної приналежності, культури, двомовності та соціальноекономічного статусу на поширеність заїкання залишається невизначеним. (DSM-5, 2013: 46-47;Gunasekaran et al, 2021).…”

Section: ключові словаunclassified

“…Воно здійснюється за допомогою технології дослідження генетичного зчеплення (Bailey-Wilson & Wilson, 2011). Дослідження генетичного зчеплення заїкання показали, що гени, причетні до нього достовірно розташовані в 7-и регіонах 6-и хромосом: 2p, 3p, 3q, 12q, 14q, 15q та 16q (Gunasekaran et al, 2021). Навіть якщо в кожному виявленому регіоні буде ідентифіковано хоча б по одному генові, причетному до заїкання, то воно буде визначатися ще 7-ма генами.…”

Section: ключові словаunclassified

“…Точна локалізація гена в хромосомі, його молекулярна структура, мутації та їх позиції в структурі гена визначаються за допомогою технології дослідження загальногеномних асоціацій (genome-wide association studies, GWAS) (Uffelmann et al, 2021). На цей час ідентифіковано 4 гена, причетних до заїкання: GNPTAB, GNPTG, NAGPA та AP4E1 (Frigerio-Domingues & Drayna, 2017; Gunasekaran et al, 2021). Подаємо опис цих генів щодо заїкання.…”

Section: ключові словаunclassified

“…Варто зазначити, що різні особи, вражені заїканням, можуть нести різні набори мутантних варіантів, наприклад, p. Glu1200Lys та p. Thr644Thr у гені GNPTAB і p. Asn495Asn у гені NAGPA, або p. Thr644Thr у гені GNPTAB, р. Ile268Leu у гені GNPTG і p. Asn495Asn у гені NAGPA, або лише p. Asn495Asn у гені NAGPA тощо (Gunasekaran et al, 2021).…”

Section: ключові словаunclassified

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Genetics of Stuttering

Pomohaibo¹,

Berezan²,

Petrushov³

2023

ПІO

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Stuttering is characterized by frequent repetition or lengthening of sounds, syllables or words, or by frequent hesitations or pauses that disrupt the rhythmic flow of speech. It may be accompanied by movements of the face and/or other parts of the body that coincide in time with the repetitions, prolongations, or pauses in speech flow. The prevalence of stuttering ranges from 0.3% to 5.6%. Usually for 80%-90% of patients stuttering starts gradually when children are 2-7 years old. Longitudinal research shows that 65% -85% of stuttering children recover. The rate of heritability of stuttering is about 70%, indicating that almost one third of the disorder is caused by environmental factors. Currently four stuttering genes have been identified that are involved in intracellular metabolism: GNPTAB, GNPTG, NAGPA and AP4E1. The disorder is caused by single nucleotide synonymous or missense mutations in the exons of these genes. Different people affected by stuttering can carry different sets of mutant variants ‒ from one to several. The effect of the identified genes on neurobiological processes in the human brain and on the development of stuttering remains unknown. So far it has only been discovered that stuttering occurs due to lysosomal dysfunction, which adversely affects the organization of neurofilaments of speech neural networks. The contribution of identified genes to stuttering cumulatively is only 20%. There were identified also 9 candidate stuttering genes (FADS2, PLXNA4, CTNNA3, ARNT2, EYA2, PCSK5, SLC24A3, FMN1 and ADARB2) and 7 regions of 6 chromosomes (2p, 3p, 3q, 12q, 14q, 15q and 16q) reliably linked to this disorder. Further successful genetic studies of stuttering are needed to improve our understanding and treatment of this long-enigmatic disorder.

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Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering

Nandhini Devi,

Yadav,

Jayashankaran

et al. 2024

Annals of Human Genetics

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BackgroundDevelopmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in GNPTAB, GNPTG, and NAGPA involved in lysosomal pathway and AP4E1, IFNAR1, and ARMC3‐signaling genes reported till date explain only ∼2.1% – 3.7% of persistent stuttering cases.AimWe aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (n = 27) and further validation on additional extended family members (n = 21).Materials & MethodsWe employed hypothesis‐free and pathway‐based analyses.ResultsA novel heterozygous exonic variant NM_016256.4:c.322G > A in NAGPA with reduced penetrance and predicted pathogenicity segregated with the phenotype in a large subset of the family. Reanalysis to identify additional disease‐causing variant(s) revealed exonic heterozygous variants each in RIMS2 and XYLT1 in severely affected members; and IGF2R variant in a small subset of the family. Furthermore, pathway‐based analysis uncovered NM_022089.4:c.3529G > A in ATP13A2 (PARK9) in affected members; and variants in GNPTAB and GNPTG of minor significance in a few affected members.DiscussionGenotype–phenotype correlation efforts suggest that the combined effect of gene variants at multiple loci or variants in a single gene in different subsets of the pedigree (genetic heterogeneity) may be contributing to stuttering in this family. More importantly, variants identified in ATP13A2, a Parkinson's disease gene also implicated in lysosomal dysfunction, and RIMS2 suggests for the first time a likely role of dopamine signaling in stuttering.ConclusionScreening for these variants in independent stuttering cohorts would be astute.

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Evaluation of recurrent GNPTAB, GNPTG, and NAGPA variants associated with stuttering

Cited by 5 publications

References 41 publications

The Difference between Monolingual and Bilingual Stutterers: A Systematic Review

The Difference between Monolingual and Bilingual Stutterers: A Systematic Review

Genetics of Stuttering

Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering

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