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.