Journal of Fluency Disorders xxx (xxxx) xxx–xxx

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Journal of Fluency Disorders

journal homepage: www.elsevier.com/locate/jfludis

Genetic epidemiology of stuttering among school children in the

state of Tamil Nadu, India
G. Nandhini Devia, Anbupalam Thalamuthub, S. Valarmathic, N.P. Karthikeyend,
C.R. Srikumari Srisailapathya,
⁎

a
Department of Genetics, Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
b
Centre For Healthy Brain Aging (CHeBA), University of New South Wales, Sydney, Australia
c
Department of Epidemiology, The Tamil Nadu Dr. MGR Medical University, Guindy, Chennai, 600 032, India
d
DOAST (Doctrine Oriented Art of Symbiotic Treatment) Speech & Hearing Care Center and Integrated Therapy Center for Autism, Anna Nagar West,
Chennai, India

ARTICLE INFO ABSTRACT

Keywords: Purpose: Stuttering is a fluency disorder with a worldwide prevalence of 1%. Reports on the
Stuttering epidemiology of stuttering in India are limited. Our primary goal was to examine the prevalence
Parental consanguinity of the disorder among school children. The study also aimed to examine risk factors associated
Prevalence with severity and the impact of parental consanguinity in stuttering.
Familial incidence
Method: Children from 97 schools in the State of Tamil Nadu, India were screened. Extensive
Sex ratio
speech characterization, epidemiological details and three-generational pedigrees were collected
for 180 probands. The genetic basis of stuttering was examined using the analysis of genealogical
index of families (GIF), kinship group and sibling recurrence risk (SRR) measures. Regression
analysis and chi-square tests were performed to test the association of risk factors with severity of
the disorder.
Results: Among the 74,544 school children screened, the prevalence of stuttering was found to be
0.46%. Pedigree analysis revealed a positive family history in 101 (56%) probands; overall fa-
milial incidence was 11%. We observed an overall male-favored sex ratio (4:1). Familial ag-
gregation (GIF = 442.60, p-value < 0.001) and sibling recurrence risk ratio (Ks = 0.197,
SD = 0.041) was high among consanguineous families. Severity of stuttering was strongly as-
sociated with gender and moderately associated with age at onset.
Conclusion: The prevalence of stuttering in Tamil Nadu is estimated for the first time in this
study. High familial incidence, familial aggregation and sibling recurrence risk ratio point to the
presence of a genetic basis. Familial aggregation was high among consanguineous families al-
though consanguinity did not seem to play a role in severity.

1. Introduction

Stuttering is a speech disorder which usually begins in early childhood. The worldwide incidence is estimated to be 5% but nearly
80% of cases recover spontaneously (within 18 months) without any treatment, and 20% remain persistent (stutter > 36 months)
(Gordon, 2002; Månsson, 2000). At all ages more males than females are affected.

Corresponding author.
⁎

E-mail addresses: srikumarinandhini@gmail.com (G. Nandhini Devi), a.thalamuthu@unsw.edu.au (A. Thalamuthu),

valarmathi.s@tnmgrmu.ac.in (S. Valarmathi), karthik28@hotmail.com (N.P. Karthikeyen), crsrikumari@gmail.com (C.R. Srikumari Srisailapathy).

https://doi.org/10.1016/j.jfludis.2018.10.001
Received 28 February 2018; Received in revised form 6 August 2018; Accepted 5 October 2018
0094-730X/ © 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Nandhini Devi, G., Journal of Fluency Disorders, https://doi.org/10.1016/j.jfludis.2018.10.001
G. Nandhini Devi et al. Journal of Fluency Disorders xxx (xxxx) xxx–xxx

In a comprehensive review on the epidemiology of stuttering, Yairi and Ambrose (2012) reported more than 40 prevalence studies
worldwide. The prevalence rates ranged from 0.3% to 5.6% and the average prevalence over the lifespan may be lower than the
commonly cited 1% that was noted in the last century. In India, to date only three studies have documented the incidence and
prevalence of stuttering in an indirect manner, where the prevalence of stuttering was reported from studies on psychiatric and
communication disorders. An early pilot survey on the incidence of speech handicaps among Indian school children in New Delhi,
from kindergarten to seventh grade, indicated a prevalence of 1.2% for stuttering (Hegarty, 1968). A National survey conducted by
the Government of India on various disabilities reported 0.4% prevalence among disabled persons (India, NSSO, 2003). An epide-
miological study of child and adolescent psychiatric disorders reported a prevalence rate of stuttering of 1.5% among 4-16 year-olds
from urban, slum and rural areas of Bangalore, Karnataka (Srinath et al., 2004). However, the All India Institute of Speech and
Hearing (AIISH) found 10% stuttering among children with communication disorders (Subramanian & Prabhu, 2005).
The etiology of stuttering is still largely unknown although several risk factors have been reported, including low birth weight
(Boulet, Schieve, & Boyle, 2011; McAllister & Collier, 2014), age and manner of onset (Yairi & Ambrose, 2005), gender (Ambrose,
Cox, & Yairi, 1997), severity (Prasse & Kikano, 2008), positive parental stuttering/family history (Kloth, Janssen, Kraaimaat, &
Brutten, 1998), and attitude towards the disorder and treatment (Bothe, Davidow, Bramlett, & Ingham, 2006; Subramanian & Prabhu,
2005). Investigation of these risk factors may help in identifying stuttering earlier, thus enabling early treatment.
The age at onset for developmental stuttering is 2-5 years, whereas the adult-onset type is considered as acquired and may be
further sub-classified as neurogenic and psychogenic (Wittke-Thompson et al., 2007). Developmental stuttering mostly affects
children, with a gradual onset of the disorder (Prasse & Kikano, 2008). Age at onset is reported to be associated with persistency (Cox,
Kramer, & Kidd, 1984), and Yairi and Ambrose (2005) reported that a trend for persistency is associated with later age at onset. The
phenomenon of spontaneous recovery has been extensively discussed in the scientific literature (Bloodstein, 1995).
At all ages there is a skewed sex ratio with a preponderance of males affected (Drayna & Kang, 2011; Gordon, 2002). The higher
chronicity of the disorder among males than females generally has been explained by the fact that the females have a greater
tendency for recovery than males (Ambrose et al., 1997).
Speech assessment establishes the severity of dysfluency, which can be classified as normal, mild and severe. In severe cases,
stuttering occurs in almost every phrase and it may be accompanied by secondary behaviors such as eye blinking, head jerks, lip
pressing etc., resulting in embarrassment and fear of speaking (Prasse & Kikano, 2008).
Several studies, including twin and family reports, have demonstrated the involvement of genetic factors in the transmission of
susceptibility to stuttering, therefore family history is an important risk factor (Frigerio-Domingues & Drayna, 2017). Statistical
evidence for both a single major locus and a polygenic component have been advocated in persistent and recovered stuttering
(Ambrose et al., 1997).
Consanguinity is the union of individuals genetically related to each other as close or closer than second cousins (F ≥0.0156).
Intracommunity marriage is the norm in most regions that favor consanguineous marriages, e.g. within castes in India, and in such
circumstances gene flow between communities is highly restricted. Consanguinity has a greater influence on the etiology of complex
diseases when rare autosomal recessive alleles are involved. Where both gene-gene interactions and non-genetic factors in prenatal
and postnatal life contribute to the disease phenotype, the expression of a single causative gene is improbable (Bittles & Black, 2010).
To identify the genetic loci associated with stuttering, linkage studies have been performed in multiplex families, i.e. with
multiple affected family members. Although the initial results were suggestive they could not be replicated (Shugart et al., 2004;
Suresh et al., 2006; Wittke-Thompson et al., 2007). However, subsequent studies found definitive evidence on chromosomes 3, 12
and 16 in a large highly inbred Pakistani family (Raza, Riazuddin, & Drayna, 2010; Raza, Amjad, Riazuddin, & Drayna, 2012; Riaz
et al., 2005) and on chromosomes 2, 3, 14 and 15 in a large Cameroon family (Raza et al., 2013). Fine mapping of a Pakistan family
(Kang et al., 2010) identified the gene GNPTAB and two additional causative genes, GNPTG and NAGPA. Using whole exome se-
quencing, Raza et al. (2015) further identified AP4E1 gene variants that co-segregate with persistent developmental stuttering in a
large Cameroon family, and the combined contribution of these four genes, GNPTAB, GNPTG, NAGPA and AP4E1, to stuttering was
estimated to be 20%. The four genes all pointed to a single process, i.e. intracellular trafficking deficits, that are an emerging concept
in neurological disorders (Frigerio-Domingues & Drayna, 2017). Only one genome-wide association study (GWAS) on stuttering has
so far been completed. Although no significant GWAS hits were found, nine suggestive candidate genes (FADS2, PLXNA4, CTNNA3,
ARNT2, EYA2, PCSK5, SLC24A3, FMN1, ADARB2) involved in neural pathways were identified in persistent developmental stut-
tering, together with a SNP (rs2573111) upstream of a small non-coding RNA (RNU6-259P) (Kraft, 2010).
Numerous different directions have been followed in research and into the treatment of stuttering, with varying attitudinal dif-
ferences across cultures. Behavioral, cognitive, pharmacological and related treatments are available for stuttering (Bothe et al.,
2006) and, besides speech-language pathologists, in India psychologists, psychiatrists and practitioners of alternative systems of
medicine also treat the disorder (Subramanian & Prabhu, 2005). Thus it is important to know whether our particular population is
aware of the available treatment options, and the manner in which the disability is perceived.
Thus to the best of our knowledge this is the first study to estimate the prevalence of stuttering in school children in Tamil Nadu,
India, and our study also aims to characterize the risk factors that are associated with severity of stuttering. Despite three large studies
conducted on school children worldwide (Boyle et al., 2011), to date the role of consanguinity has not been examined. Therefore this is
the first such study to examine the possible impact of consanguinity on familial aggregation in stuttering.

2. Methodology

The study was approved by the Institutional Human Ethical Committee (Approval No: UM/IHEC/10-2017-I). Of a total of 100

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schools approached over a five-year period, 97 schools consented to participate in the screening for stuttering. Overall, we screened
74,544 students and identified 342 CWS (children with stuttering). The schools were recruited from two cities, Chennai (n = 78) and
Salem (n = 19). They represent both government and private educational sectors, with students from different socio-economic
backgrounds.

2.1. Proband ascertainment and assessment

The Principals of the schools were approached with a formal letter outlining the proposed study and the objectives of research
were explained to the class teacher. In India, although many teachers instruct a class for various subjects, there will be a designated
class teacher who co-ordinates, prepares the progress reports and interacts closely with every student of that class and their parents.
In other words, this class teacher has maximum interaction with each student in multiple dimensions and meets them on a daily basis.
Based on their personal assessment, the class teachers were asked to provide a list of students with any perceived slight problem in
communication and speaking, including those who were constantly reluctant to speak. The clinical investigator trained the in-
vestigators to detect CWS during the initial screening.
Children with suspected problems in speech, who were shortlisted in the first phase in accordance with the teachers' referral, were
intensively analyzed for speech and non-speech behaviors associated with stuttering in a dedicated room allocated by the school
authorities. These students were systematically evaluated by trained investigators in face-to-face interview. Three tasks were ad-
ministered to each of the students: casual conversation to elicit spontaneous speech, followed by a reading and a picture task. They
were assessed for stuttering behaviors, including:
Primary Behaviors

(i) Verbal (Repetition - part word/full word, Prolongation, Hesitation, Stress, Starters, Blocks)

Secondary behaviors

(ii) Hidden (Situational fear, Blocks, Struggle or Forcing, Avoidance of words)

(iii) Nonverbal (Physical concomitants, Facial expression, Gestures, Eye blinking, Gasping)

Other concomitants

(iv) Phonology
(v) Articulation

The probands were classified as mild, moderate or severe stutterers depending on their performance with respect to the instances
of speech repetition, prolongations, blocks and hesitations observed in the interview. Mild stuttering was diagnosed if there were less
than 20, moderate if 21–50 and severe if more than 50 instances of repetition, prolongations, blocks and hesitations were observed.
To understand the effect of stuttering on the social behavior of the proband, their academic and extracurricular performance was
evaluated with the help of the class teacher. Associated symptoms such as embarrassment and anxiety were also discussed. Some
85.7% of students who were referred by the teachers were confirmed to be stuttering. Further CWS identified in this manner were
verified by speech pathologists using video samples to score for primary and secondary behaviors. However, in some schools we were
not able to undertake videotaping and in such instances we had to resort to audio, along with manual scoring for the secondary
behaviors.

2.2. Data on risk factors

The parents of the probands were personally consulted by the investigators in their homes. With their consent a structured
interview was conducted to collect information on important risk factors for stuttering that included: pre- and perinatal life; type of
dysfluency; physical and emotional stress; handedness; age and nature of onset in stuttering; parental marriage type, i.e. con-
sanguinity; family history; family attitudes, including information on how they coped with the stuttering in daily life, their awareness
of management/treatment; and personal reactions, e.g. anxiety, shyness. A standard set of questions was used to elicit this in-
formation.

2.2.1. Pedigree drawing

Pedigrees were drawn to include first degree (children, parents and siblings), second degree (grandparents, uncles, aunts, nieces
and nephews) and third degree (cousins) relatives. Other affected members in the family of each proband beyond the nuclear family
were not personally assessed due to their unavailability or time constraints. However, additional affected members of the extended
family and their persistent/recovery status were recorded, after thorough probing and confirmation by parents and other informants
in the family. Nevertheless, it is possible that recovery status was under-reported.

2.2.2. Exclusion criteria

Although 342 probands were ascertained, 39 were excluded due to pre/post-stuttering epilepsy, cleft palate, ADHD, polio,

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G. Nandhini Devi et al. Journal of Fluency Disorders xxx (xxxx) xxx–xxx

Fig. 1. Flow chart depicting the study design and recruitment of 342 children with stuttering.

deafness, head injury and onset within six months of our assessment. Among the 303 probands identified, 123 families did not
cooperate after the first phase of the study. Detailed pedigrees are available for 180 probands and consanguineous status was also
recorded wherever applicable (Fig. 1).

2.3. Statistical analysis

Consanguinity was measured by the coefficient of inbreeding (F), the probability that a homozygote has received both alleles at a
locus from the same ancestral source, referred to as identity by descent. Coefficients of inbreeding were calculated for each type of
consanguineous union: uncle-niece, F = 1/8; first cousin, F = 1/16; first cousin once removed, F = 1/32; second cousin, F = 1/64;
second cousin once removed, F = 1/128; and beyond second cousin, F < 1/256 (Nussbaum, McInnes, & Willard, 2007). The mean
coefficient of inbreeding (α) was estimated for the population using α =ΣPiFi; where Pi is the proportion of a certain type of
consanguineous marriage and Fi is the coefficient of inbreeding of that specific type of consanguineous marriage. The average
inbreeding coefficient (α) in human population is generally less than 1 per 1000 (Slatis, 1973).
The sibling recurrence risk, i.e. the probability of being affected if a sibling is affected was calculated, correcting for single
ascertainment bias (Olson & Cordell, 2000). The sibling recurrence risk ratio is defined as λs=Ks/p, where Ks is denoted as the
proportion of affected siblings among all siblings of affected persons in a population, and p is the population prevalence of stuttering.

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The association of risk factors for severity of stuttering was examined using logistic regression (glm function in R) and proportional
odds logistic regression (polr function in R package MASS) models.
Familial aggregation was examined using the genealogical index of families (GIF), kinship group, and probability of familial
clustering (PFC) tests as implemented in the R package FamAgg. The GIF is the average kinship coefficient KF, i.e. the probability that
two alleles drawn at random from two individuals are identical, between all possible pairs of affected individuals multiplied by 105.
The p-values were obtained by creating a null distribution of matched unaffected pairs. We used 1000 simulations to generate the
statistics under the null distribution. The kinship group test identifies kinship coefficient-based clusters of closely related affected
individuals (Rainer et al., 2016), and its significance was evaluated using the null distribution based on random sampling of in-
dividuals. The FamAgg package also provides a calculation of PFC using the function implemented in the R package gap (Zhao,
2007). The PFC was calculated using multinomial distribution of affected cases within families (Yu & Zelterman, 2002). Due to the
high computational burden for this procedure, the analysis was restricted to pedigrees with fewer than 22 individuals. All of the
statistical analyses were performed using the R package (R Core Team, 2016).

3. Results

3.1. Overall prevalence

We screened 74,544 children in the age group 2.5–16 years and found a prevalence of stuttering of 0.46% (N = 342 CWS) (95%
CI = 0.41% - 0.51%).

3.2. Risk factors

The male/female sex ratio within the probands was 6:1 (Table 1). The sex ratio by age groups shows an increase in sex ratio from
younger to older age groups (Table 2). Among relatives of male probands it was 4:1 and for relatives of female probands it was 2:1
(Table 3). For affected first-degree relatives the sex ratios varied: male probands had a higher proportion of affected male relatives
(M/F = 2:1) while female probands had more affected female relatives (M/F = 0.5). Determining recovery is not easy and often
requires some sort of follow up over time, in our study we have recorded the recovery status retrospectively from informants. In most
cases the informants were the parents of the proband. Where possible close associates living along with the family such as the
grandparents reinforced the information. The recovery rates reported among the families of male and female probands were 23% and
38% respectively.
The mean age at onset of stuttering among all the probands was 4.7 years (SD = 2.51). The difference in the mean age of onset
between males (Mean = 4.8; SD = 2.585) and females (Mean = 4.0; SD = 1.936) was not significant (t = 1.648; P = 0.108). Some
76.6% of CWS were dysfluent at < 6 years and 15.6% at > 6 years. For 7.8% of the study sample the age of onset was not known. The
frequency of the ages of onset among males and females showed two peaks at the 3rd and 5th years respectively. The manner of onset
was gradual for 71.6% of probands (Table A1).
On analyzing the pedigrees, 56% had a positive family history (n = 101/180) and the remaining (n = 79) were sporadic, with a
single affected subject in the family. The distribution of affected members among first-, second- and third-degree relatives was 38.2%
(68/178), 34.8% (62/178) and 26.9% (48/178) respectively. The familial incidence was 11% (178 were stuttering relatives out of
1596 relatives ascertained); 38% of whom were first degree relatives (n = 68) of the probands. The proportion of male stuttering
relatives (0.17) was significantly higher than that of female stuttering relatives (0.05) (z = 7.6144; P = 0.0000) (Table 4).
CWS born to non-consanguineous (78%) and consanguineous (22%) parents are shown in Table 5. Among 79 sporadic cases, 11
had consanguineous parents. However, as expected parental consanguinity was higher (71.8%) in familial cases than in sporadic
(28.2%). The overall coefficient of inbreeding (α) was 0.0165 (Table 6). Stuttering probands were distributed across the different
religions (Table A2). The coefficient of inbreeding (α) for Hindus was 0.0137, 0.0207 for Christians and 0.0088 for Muslims (Table
A3).
Birth order and distribution of sibship size determine whether CWS are randomly distributed among the birth ranks: 43.3% were
first-born, 33.3% were second, 11.0% were third and 8.3% were fourth-born. The average sibship size was 3.0 (SD = 1.0).
Approximately one in eleven (9/101) subjects were a “single stuttering child” family (8.9%). The majority of families has a sibship
size of two (46.5%), 21.8% had 3 sibs, with the frequency of 4–8 siblings gradually decreasing (Table 7).
An increased ratio of males to females was consistently observed in all sibship sizes, including the single affected families. Among
the 101 probands with a family history, 60.4% (61 probands) had normal speaking parents. The remaining 38.6% had either one

Table 1
Comparison of sex ratio (familial Vs sporadic) among children with stuttering.
Sex Familial Sporadic Total

Males 86 68 154
Females 15 11 26
Total 101 79 180
M/F 6:1 6:1 6:1

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Table 2
Frequency distribution of children with stuttering in relation to age and sex ratios.
Age (Yrs) Male Female Total M/F

2-5 5 3 8 1.6
6-10 32 14 46 2
11-15 92 10 102 9
16-20 24 – 24 24
Total 153 27 180 6

Table 3
Frequency of stuttering among the relatives of male and female probands.
Probands Affected male relatives/total male Affected female relatives/total female Total affected relatives/total relatives M/F ratio
relatives relatives

Male (153) 123/690 = 0.18 34/675 = 0.05 157/1365 = 0.12 3.6

Female (27) 16/123 = 0.13 10/108 = 0.09 26/231 = 0.11 1.6
Total 139/813 = 0.17 39/783 = 0.05 178/1596 = 0.11 3.6

Table 4
Frequency of stuttering among first, second and third degree relatives of probands with a positive family history.
P First degree relatives Total Second degree relatives Total Third degree relatives Total Total Males Total Females Total relatives

Male (M) Female (F) Male (M) Female (F) Male (M) Female (F)

M 43/165 14/146 57/311 43/394 14/407 57/801 37/131 6/122 43/253 123/690 34/675 157/1365
= 0.26 = 0.1 = 0.18 = 0.11 = 0.03 = 0.07 = 0.28 = 0.05 = 0.17 = 0.18 = 0.05 = 0.12
F 4/23 7/31 11/54 9/77 1/62 10/139 3/23 2/15 5/38 16/123 10/108 26/231
= 0.17 = 0.23 = 0.2 = 0.12 = 0.02 = 0.07 = 0.13 = 0.13 = 0.13 = 0.13 = 0.09 = 0.11
T 47/188 21/177 68/365 52/471 10/469 62/940 40/154 8/137 48/291 139/813 39/783 178/1596
= 0.25 = 0.12 = 0.19 = 0.11 = 0.02 = 0.07 = 0.26 = 0.06 = 0.16 = 0.17 = 0.05 = 0.11

Table 5
Distribution of parental consanguinity among sporadic and familial stuttering probands.
Group Sporadic Familial Total

Consanguineous 11 (28.2%) 28 (71.8%) 39

Non consanguineous 68 (48.2%) 73 (51.8%) 141
Total 79 (43.8%) 101 (56.1%) 180

Table 6
Frequency of parental consanguinity and the coefficient of inbreeding among stuttering probands.
Nature of relationship M F Total 180 % Inbreeding coefficient (f)

Non- consanguineous 126 15 141 78

consanguineous 29 10 39 22
Uncle niece 6 5 11 6.6 0.0083
Aunt-nephew 1 1
First cousin 17 4 21 11.6 0.0073
First cousin once removed 3 1 4 2.2 0.0007
Second cousin 2 2 1.1 0.0002
Mean co-efficient of inbreeding (α) 0.0165

(Affected x Normal = 39) or both (Affected x Affected = 1) parents affected.

Despite linguistic homogeneity in the study population, the cultural barrier created by caste endogamy in the majority Hindu
population may prevent gene flow between sub-communities and thus could be a partial contributor to genetic diversification. Only
4.4% of the affected children were born to parents in inter-caste marriages. Thirty-six endogamous castes were recorded among
Hindu probands (67.9%), but in 18.3% of cases no specific caste was reported. In addition, probands belonging to Christian (2.2%)
and Muslim (7.2%) communities also were recorded (Table A4).
Speech therapy awareness was conspicuously absent in 84% of probands' families. Attitudinal inhibitions, such as avoidance of
speech with strangers, were observed. Coping involved interjections and word substitutions. Stress factors such as prenatal

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Table 7
Distribution of sibship size and the number of stuttering probands born to consanguineous and non-consanguineous parents.
Sibship size No. of sibships No. of affected (r)

r=1 r=2 r=3 r=4

C NC C NC C NC C NC C NC

1 3 5 3 5
2 10 35 7 31 3 4
3 5 20 3 12 2 8
4 7 10 4 7 2 3 1
5 1 1 1 1
6 1 2 1 1 1
7
8 1 1
Total 28 73 18 57 9 16 1

Note: r= no. of affected children; C = Consanguineous; NC = Non Consanguineous.

complications, speech delays, multilingual environment in the educational setting, social/parental pressure and illness were at-
tributed as a reason for stuttering in their children. Only 20.5% of the parents discussed such stress factors (Table A5).

3.3. Risk factors for severity of stuttering

The age of onset, sex, family history, and consanguinity were examined for their association with severity of stuttering (Table 8).
The distribution of degree of severity among the probands (n = 180) showed that in 51.6% of cases stuttering was mild, with 22.7%
moderate and 25.0% severe (Table A6). Severity was grouped into three groups (mild, moderate and severe) and two (mild, moderate
versus severe) factors respectively, and tested for association with risk factors using proportional odds logistic regression and logistic
regression models.
There was a suggestive evidence for association of age and sex with severity (unadjusted p-value < 0.05) under logistic regression
model. However, sex would be the only factor associated with severity, if a conservative Bonferroni multiple-test correction was
applied to the p-values, assuming 4 independent tests. As shown in Table 8 the severity among males was significantly higher than in
females. The age of onset among the severe form of stuttering was slightly higher compared to cases of mild stuttering. Logistic
regression and proportional odds logistic regression gave similar results.

3.4. Familial aggregation

3.4.1. Genealogical index

As expected the GIF (mean KF x 105) of all pedigrees was 84.60 (p-value = 0.001 based on 1000 simulations) and within con-
sanguineous families (n = 39) the GIF was 442.60 (p-value < 0.001), indicating higher kinship among the affected individuals within
consanguineous families. The GIF among non-consanguineous pedigrees (n = 141) was estimated to be 93.02, which was not sta-
tistically significant (p-value = 0.127) implying higher kinship among the affected individuals within consanguineous families.

3.4.2. Kinship group test

The kinship group test was used to identify the families with a large proportion of closely related affected individuals. From all the

Table 8
Risk factors for severity of stuttering.
VariableSeverity Mild Moderate Severe B (SE)* P* B (SE)** P**

Sex
Male 74 37 44 −1.37(0.56) 0.01 −1.35(0.55) 0.01
Female 19 4 2

Family History
No 38 19 22 −0.52(0.33) 0.12 −0.52(0.31) 0.09
Yes 55 22 24

Consanguinity
No 74 32 35 0.64 (0.42) 0.12 0.59(0.38) 0.12
Yes 19 9 11

Age at onset 4.25(2.1) 5.59(3.0) 4.92(2.72) 0.15(0.07) 0.03 0.10(0.06) 0.07

Note: *B(SE), p-value under logistic regression; **B(SE), p-value under proportional odds logistic regression; Mean(SD) are presented for age at onset.
B-denotes the log odds ratio.

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pedigrees examined (n = 180) the test identified 14 (7.8%) which had a higher proportion of closely related affected individuals, of
which 5 (5/39 = 12.8%) were consanguineous families. When applied to consanguineous families the test identified 6 pedigrees
(5 families identified in the previous analysis plus additional family) with a higher proportion of affected individuals.

3.4.3. Sibling recurrence risk ratio

The sibling recurrence risk (Ks) estimated from the overall sample was 0.143 (SD = 0.019), for consanguineous families Ks was
0.11(SD = 0.016), and for non-consanguineous families Ks was 0.197 (SD = 0.017). The Ks values for consanguineous and non-
consanguineous families were significantly different (p-value = 0.04). There was a slight increase in the sibling recurrence risk (Ks)
estimated within the male sib-pairs 0.17 (SD = 0.027) compared to all sib-pairs, but Ks could not be estimated for female sib-pairs
pairs since they were not observed in the cohort.
Within the full sample, the sibling recurrence risk ratio λs=Ks/p, assuming 1% prevalence of stuttering, was 14.30 [95% CI=
(10.48, 18.12)], and within consanguineous families Ks was 19.68 [95% CI (11.65, 27.72)]. These estimates would double if the
prevalence observed in the current sample (∼0.5%) was used.

4. Discussion

Every country needs a credible estimate for the prevalence of stuttering to frame its national policy and effectively address
management of the disorder. Our study is the first targeted approach to examine the prevalence of stuttering in India. The strengths of
the study include broad and inclusive subject ascertainment, a relatively large sample size, and professional speech evaluation that
generated high quality phenotype information. Stuttering was confirmed by investigators/speech pathologists, reconfirmed by
parents, teachers and by self-report where available. Yet those who went undetected, e.g. with mild CWS, may contribute to a slight
underestimate of the overall prevalence.
It has been reported that the prevalence of stuttering ranged from 0.3% to 15.4% across different studies (Felsenfeld et al., 2000),
and the prevalence estimate in our study (0.46%) is substantially lower than the approximate mean prevalence of 1% that has been
cited (Bloodstein & Bernstein Ratner, 2008). If the prevalence is indeed less than 1%, natural recovery may have ameliorated a
greater initial risk of exhibiting stuttering (Yairi & Ambrose, 2012). Interestingly, a study that covered the life span from 1 to 99 years
yielded an overall prevalence of 0.72%, with variation observed for discrete age groups (Craig, Hancock, Tran, Craig, & Peters, 2002).
Gender is one of the strongest predisposing factors. Kidd (1984) suggests that the gender effect requires a lower threshold for
males with females requiring more genetic loading and/or environmental forces for expression of the disorder. The increase in the
male to female ratio with age is critical in understanding persistence and recovery (Ambrose et al., 1997). We found that recovery
reported among female affected relatives of the probands in general was high, and also observed that the classical male-favored sex
ratio increased with age to 9:1. The sex ratio of affected relatives is 4:1 in the families of male probands but decreases to 2:1 in the
families of female probands. Although mild stuttering is difficult to recognize (Mellon, Umar, & Hanson, 1993), we observed a greater
proportion of mild than moderate and severe types of the disorder. Examining the sex ratios in familial and sporadic probands,
Drayna, Kilshaw, and Kelly (1999) observed that in familial cases the sex ratio is approximately equal (1.5:1), but in sporadic families
the male to female ratio was much higher (7:1). By comparison, we observed an unchanged sex ratio in both familial and sporadic
(6:1) cases.
Reports on onset are variable, with estimates suggesting that the highest risk is observed under 3–8 years (Andrews & Harris,
1964; Onslow, 1992; Yairi & Ambrose, 1999). Our observations concur with Yairi and Ambrose (1999), having two peaks at 3 and 5
years with the maximum at 3 years. In the present study 7.8% were CWS with age at onset greater than 10 years. This may be due to
interiorized stuttering, i.e. subjects who avoid speech and are unaware of their stuttering, which is difficult to distinguish from
acquired stuttering (Michael & Clifford, 1983).
Familial stuttering shows a relatively early and gradual onset while sudden onset is invariably associated with neurological
damage (Yairi & Ambrose, 1992). In our study, while gradual onset was common in familial cases, sudden onset occurred in both
familial and sporadic cases. However, our results may be confounded by inaccurate recall of parents in reporting age/manner of
onset.
Familial incidence of stuttering (11%) is higher than the general population incidence (1%) supporting the genetic nature of
stuttering. Male and female CWS had equal frequencies of affected relatives, with first degree relatives quite common, and in many
previous studies a positive family history of 20–74% has been reported (Bloodstein, 1995). Kidd, Heimbuch, and Records (1981)
found that the relatives of female probands were affected more frequently than the relatives of male probands, but in our study male
and female CWS had equal frequencies of affected relatives, matches the results reported by Ambrose, Yairi, and Cox (1993). Sporadic
cases challenge the distinction between genetic and non-genetic that can ultimately be resolved by further studies.
Our population is characterized by substantial consanguinity, which can influence the expression of genetic disorders. However, it
is important to emphasize that in assessing the impact of consanguinity on any disorder, a clear causal relationship needs to be
established rather than reliance on speculation driven solely by the presence of close kin relationships in family pedigrees.
Although three large studies have reported on stuttering in school children worldwide (Boyle et al., 2011), the possible role of
parental consanguinity in stuttering has not previously been examined. We comprehensively evaluated parental consanguinity with an
overall estimate of the mean coefficient of inbreeding (α = 0.0165), and observed a consanguinity rate of 22.6% among the parents
of CWS, which closely approximates to that of general population of Tamil Nadu (22.4%) (Ramesh, Srikumari, & Sukumar, 1989). To
better understand the influence of parental consanguinity, we compared our data with local and national level information on
consanguineous marriage in India. All these reports are on the general population, i.e. without any known morbidity, and in South

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India consanguinity ranged from 7.5% (Kerala) (Bittles, Grant, Sullivan, & Hussain, 2002) to 54.9% in Pondicherry (Puri, Verma, &
Bhargava, 1978) and upto 50% in rural Tamil Nadu (Rao, Inbaraj, & Jesudian, 1972).
The coefficient of inbreeding (α) was highest among Hindus, because of the high rates of first cousin (33%) and uncle-niece
marriages (33%). Although normal speaking parents predominated in our stuttering cohort, reflecting genetic heterogeneity, pro-
bands with at least one parent affected were not uncommon.
Stuttering probands included more first-born children, providing further evidence disproving the theory that stuttering is a
learned behavior (Wingate, 1971). Gladstien, Seider, and Kidd (1981) reported that birth order and age of separation were not sig-
nificant factors in the frequency of stuttering. The question of caste is potentially very interesting, but because of the large number of
Hindu castes represented (n = 36) and the low prevalence of stuttering no conclusions can be drawn.
Stuttering has been found to seriously affect personal relationships, limit career choices and lessen the individual’s quality of life.
Understanding attitudinal differences like behavioral reactions and the interaction with parents would help in counseling and the
management of risk factors. In our population an awareness of speech therapy was poor, therefore there is a need to disseminate such
information among probands/parents. Without appropriate education, parents tend to blame the child for being dysfluent on pur-
pose. Hence counseling was directed to both the parent and child. We found CWS were withdrawn in speech activities. Interestingly,
a majority of parents attributed prenatal elements as major contributors to stuttering. A previous study (Yairi, Ambrose, & Cox, 1996)
on environmental influence was inconclusive.
On assessing the risk factors associated with severity, sex was significantly associated with severity with female probands more likely
to have a mild form of the disorder. A moderate effect was observed for increased severity with older age of onset. Family history and
consanguinity within the pedigrees of probands were not associated with the severity of stuttering. This supports the findings of Yairi
and Ambrose (1999) that stuttering tends to cluster in families whereas severity does not. Thus, although there is an underlying
genetic basis for stuttering, environmental factors may influence severity.
The clustering of stuttering individuals was present in the analyzed pedigrees, especially within consanguineous families. As
expected, the kinship group test identified large proportions of closely related affected individuals in consanguineous families. The
sibling recurrence risk is high for consanguineous families and differs significantly from non-consanguineous counterparts. These
tests provide evidence of the genetic nature of the disorder, indicating that a rare gene variant may be responsible for its expression.
However, since the risk is quite minimal, the influence of environmental factors such as epigenetic factors or gene-environment
interactions cannot be ignored. The impact of consanguinity may have a very small effect in the disorder if it is due to high levels of
homozygosity in minor alleles contributing the phenotype.

4.1. Limitations

Limitations of the work include recruitment of children from only two areas of Tamil Nadu (Chennai and Salem). Therefore, these
results may not apply to other regions of India or be applicable to other ethnicities. By combining the data from Chennai and Salem it
was assumed that there were no differences between the two populations that might influence stuttering. Referral by class teachers
might have contributed to a slight underestimate in stuttering prevalence. Only a moderate sample size of 180 probands was included
for the detailed analysis and this may have implications for statistical power, e.g. the familial aggregation analyses performed may
have been limited by the sample size. Despite these limitations, this is the largest study to date on stuttering performed in India and
the first to examine the influence of consanguinity.

5. Conclusions

Epidemiological studies help in establishing the burden of disease and also in identifying its risk factors. The prevalence of
stuttering observed in Tamil Nadu (0.46%) indicates its relatively low occurrence in the overall community. Gender and increased
age at onset were associated with severity of stuttering, whereas family history and consanguinity were not. Familial incidence,
aggregation and sibling recurrence risks confirm the role of genetic factors in the etiology of stuttering in this population. Although
the sibling recurrence risk ratio was higher within consanguineous than non-consanguineous families, the additional risk was
minimal in general terms given the heterogeneity of this complex disorder.

Conflict of interest

The authors have no potential conflicts of interests to disclose.

Acknowledgements

We wish to record our profound gratitude to Prof. Alan Bittles, Murdoch University, Australia, for his help in the plan of data
analysis, critical comments on the results and discussions and for the scientific editing of this manuscript. We also appreciate Dr.
Karen Mather, University of New South Wales, Australia, for her suggestions to improve the manuscript.
This work was supported by UGC Research Scientists Scheme (F. 8-17(SC)/90(SA-II), University Grants Commission–Special
Assistance Programme (UGC-SAP: No. F.3-6/2013 (SAP-II)); Department of Science and Technology - Fund for Improvement of
Science & Technology (DST-FIST-II: LSI-499/2011(FIST-II)); UICIC, University of Madras. ND has been supported by CSIR SRF

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fellowship (09/115(0777)/2016-EMR-1). We are greatly indebted to schools, children with stuttering and their families. We also wish
to acknowledge the contributions of Dr. R. AnuRadha, Dr. E. Sindhuja, Ms. N. Malathy & Ms. P. Annapoorani who helped in as-
certaining CWS.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jfludis.2018.
10.001.

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Ms. G. Nandhini Devi holds her Masters in Biomedical Genetics. She is currently a CSIR senior research fellow pursuing PhD in the University of Madras and has been
working on stuttering genetics.

Dr. Anbupalam Thalamuthu is a biostatistician currently working exclusively in genomics and epigenomics studies in Centre For Healthy Brain Ageing (CHeBA),
University of New South Wales, Sydney, Australia.

Dr. S. Valarmathi is a biostatistician, currently working on projects related to Research Methodology, Bio-Statistics and Survivial modeling.

Dr. N.P. Karthikeyan is practicing Otolaryngologist involved in treatment guided, molecular based research in Autism, behavior, speech and hearing disorders.

Prof. C.R. Srikumari Srisailapathy is a UGC research scientist in the Department of Genetics in University of Madras. Her broad areas of research encompass genetics
of sensory faculties of humans with emphasis on speech and hearing. She is actively leading a team that is working on a large cohort of assortative matings to
understand the real time auditory gene dynamics inspired by the stochastic models. Her team is also currently working on the molecular genetics of stuttering in large
multiplex families.

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