INTRODUCTION
Speech is a unique motor function and when affected causes both
receptive and expressive communication disorders, significantly reducing
the quality of life. Stuttering is an expressive fluency disorder,
characterized by repetitions, prolongations, blocks, along with
secondary behaviors (head jerks, lip tremors and eye blinks) and often
lead to psychological problems such as increasing
anxiety1.
Developmental stuttering arises in children of 2-5 years age group, but
most of them (80%) recover spontaneously. But there is greater chance
of recovery (male female ratio ~5:1) among
females2–4. Prevalence of stuttering ranges from
0.3% to 5.6% and the average prevalence over the lifespan may be lower
than the commonly cited 1%5. In a recent study based
on 75000 school children in India, we reported a prevalence of
0.46%6.
Research studies on the etiology of stuttering focused mainly on
neuroimaging and genetics. Most of brain imaging methods have
consistently reported structural or functional differences contributing
to inefficient communication in stuttering. It includes over activity of
the dopamine neurotransmitter7, abnormal functional
lateralization of cortical connections8, deficits in
white matter tract that connects motor and auditory structures, corpus
callosum as well as cortical and subcortical areas9.
There is also growing consensus about the genetic origin of Central
Nervous System dysfunctions 10.
Genetic dissection is challenging due to gene-gene/gene-environment
interactions, genetic heterogeneity, gender bias, incomplete penetrance
and phenocopies 11. Initial linkage studies found
suggestive evidence for chromosome regions (1, 2q, 3q, 5q, 7q, 9p, 9q,
13q, 15q, 18p, 18q, 20p) implicated in stuttering but with little
overlap across studies 12,13,14. However definitive
evidence for linkage was identified on chromosomes 3, 12 and 16 in
highly consanguineous Pakistani families15,16,17 and
on chromosomes 2, 3, 14 and 15 in a large Cameroon
family18. Although linkage studies are spread across
Hutterite, European and American population, the four genes,GNPTAB, GNPTG , NAGPA and AP4E1, identified are
restricted to two regions [Pakistan19;
Cameroon20] with distinct ethnicities. The combined
contribution of these genes were estimated to be 20%21. All these genes point to intracellular trafficking
deficits22. Indeed genomics of stuttering is an
emerging field where the involvement of new genes are yet to be
identified.
GWAS study suggested ten candidate genes (FADS2, PLXNA4, CTNNA3,
ARNT2, EYA2, PCSK5, SLC24A3, FMN1, ADARB2 and non-coding RNARNU6-259P ) involved in neural pathways23.
Mutations so far identified implicate lysosomal dysfunction but the
biological mechanisms that affect speech are under investigation. Mice
models also point to deficits in inter-hemispheric connectivity in
astrocytes of corpus callosum 24,25, thus linking
genes to brain activity. Stuttering genes GNPTAB and GNPTGwere also previously implicated in a rare lysosomal storage disorder -
mucolipidosis.
From the genetic perspective, genes identified play role in targeting
enzymes to lysosomes that is crucial for biogenesis and also in the
maintenance of myelin sheaths. From neurological perspective
hyperactivity of dopamine and the white matter abnormalities observed in
stuttering, provide a possible neurochemical basis but the effect of the
mutations in neural cell biology is still unexplored. Owing to
significant plasticity of brain it was unable to account for the
observed differences among PWS and control, as to whether they are cause
or result of stuttering26. Thus the connecting dots
between dopamine, neural circuits and cellular waste disposal is yet to
be connected.
No studies from India are available till date that implicate any genes
for stuttering. This gap motivated us to first ideally ensure the
frequency of the previously implicated genes for stuttering in our
population, before initiating advanced approaches. We evaluate the
recurrence of the reported mutations among the three reported
(GNPTAB, GNPTG, NAGPA) stuttering candidate genes in PWS from
south India. Attempts to employ identical experimental design to
concurrently verify and replicate the findings independently would on
one hand help understand ethnicity specific variations and on another
hand would also enable reproducibility of results and facilitates
pooling of data during meta-analysis.