Mutational analysis of the three putative genes in stuttering
A total of 64 unrelated probands with non-syndromic persistent
stuttering (sex ratio - 12:1; 59:5; mean age at onset of 5.13 years)
were screened for the recurrence of mutations in the three stuttering
implicated genes. Sixty seven percent (43/64) of them had family
history. More than 50% of PWS were found to be severe; 53.1%
severe (34/64), 28.1% moderate (18/64) and 18.8%
mild (12/64).
Mutation screening of the twelve specific exons previously reported
(figure 1), identified a total of 12 variants that
includes five nonsynonymous missense variants, five synonymous and two
non coding variants (tables 1 and 2; figures A1-A3). The distribution of
these 12 variants among the 64 probands are shown in figure 2a. Variants
observed in NAGPA (n=6) were higher than that of GNPTAB(n=2) and GNPTG (n=4) (figure 2b).
Only three unrelated probands (STU 29, STU 63 and STU 34), harbored
heterozygous likely pathogenic missense variants (c.3598G>A
in GNPTAB , c.802A>C in GNPTG and
c.131G>C in NAGPA respectively) with an overall
frequency of 4.7% (3/64*100) and an allele frequency of 2.3% (3/128 *
100). None of the three showed more than one pathogenic allele but there
was co-occurrence of synonymous and non-coding variants (table 3).
The two missense variants (c.139C>T & c.1394
C>T) in NAGPA, had low conservation scores and were
found in high frequency in the ExAC database supporting their benign
nature. Hence, segregation analysis and genotype-phenotype correlations
were analyzed only for the three likely pathogenic variants (figure
3-5). Only two variants (c.3598G>A and
c.802A>C) co-segregated (table 4) with the affected status,
reducing the likely pathogenic allele frequency to 1.6% (2/128 *100).