INTRODUCTION
Stuttering is a disorder of fluency that disrupts the normal flow of
speech wherein people who stutter (PWS) know what they want to say but
have trouble saying it. The condition is generally outgrown by children
but it persists in some as an enduring problem. Emergence of stuttering
is multifactorial that includes genetic, environmental and neurological
factors. Environmental factors though not a cause, can interact with
genes (cause epigenetic modifications) and may aggravate the dysfluency
under conditions of stress, anxiety and also depends on family dynamics,
child’s temperament, etc1.
The evidence for genetic factors were indicated in multiple studies
worldwide2. Worldwide search for causative genes began
with linkage studies, as applicable to any inherited disorder, to
elucidate the genetic and non-genetic etiology relevant to stuttering.
Nevertheless since stuttering is a complex trait, linkage analysis
resulted in mapping multiple loci across studies. Identification of
genes was not possible until studies focused on consanguineous
families3. The causative genes linked to stuttering
were identified to be GNPTAB , GNPTG , NAGPA andAP4E1 that explains 20% of stuttering cases4.
All these genes point to intracellular trafficking deficits, an emerging
concept in neurological disorders, implicating lysosomal dysfunction but
the mechanism linking these genes to the phenomena of stuttering is
unknown. However these deficits are said to have unique impact on
specific neurons responsible for speech. A recent mouse model study
tried to illuminate the neurons that are central to the mystery of
stuttering and indicated that abnormality lies in astrocytes (essential
for nerve activity) of corpus callosum (largest white matter structure).
This limited astrocytes population slows down inter-hemispheric
communication by a tiny bit, noticeable only in
speech5.
Speech production requires efficient communication between central
nervous system (cortical and sub-cortical regions) and peripheral
nervous system (cranial nerves that innervate respiratory, phonatory,
articulatory and resonance systems). Age of onset of stuttering
parallels the developments in anatomy of speech system, language and
articulatory skills. Interferences in these maturational processes may
contribute to stuttering, hence brain imaging studies in children could
enhance our understanding of pathophysiology6.
Brain imaging studies revealed structural and functional connectivity
differences in Children Who Stutter (CWS) involving neural networks that
support self-initiated timing of speech movements (BGTC - Basal Ganglia
Thalamo-cortical loop, SMA and Putamen) and in integration of auditory
feedback to speech motor control process. Structural (white matter)
connectivity involving corpus callosum and those among the putamen and
cortical motor and auditory regions is attenuated in the left hemisphere
in children who stutter7,8. Over activity of the
dopamine neurotransmitter has been implicated as a potential factor in
developmental stuttering9. Thus it is evident that the
problem is not confined to a single part of brain rather connecting
different parts of the brain.
The findings in stuttering research - overactive dopamine, deficits in
neural circuits and genes involved in cellular waste disposal - all
point to communication deficits. All these findings hint that stuttering
may result from slight delay in communication with different parts of
the brain.
Research studies on the genetics of stuttering in India are limited and
nearly unexplored. Our preliminary genetic epidemiology study in a large
cohort of 74,544 school children in the state of Tamil Nadu, reported
the prevalence of stuttering to be0.46% 10. Investigational mutation
screening for the recurrence of previously reported stuttering genes
showed a minimal resolution of 3.1% (2/64) that could be ascribed to
these genes but remains elusive, which is reported as the first paper in
this series.
Since stuttering is a complex trait that segregates in families,
analyzing multiplex families would help in either identification of
highly penetrant rare variants or variants that are common in affected
individuals. Subsequently this forms the concept of this paper as the
second in this series. ES was employed in two multiple affected families
from existing database10. The aim of the study is to
identify new candidate genes for stuttering, by analyzing the pathogenic
variants inherited in the multiplex families but not present in public
databases.