The Expansion of the Spectrum in Stuttering Disorders to a Novel ARMC Gene Family (ARMC3)

Abstract

Stuttering is a common neurodevelopment speech disorder that negatively affects the socio-psychological dimensions of people with disability. It displays many attributes of a complex genetic trait, and a few genetic loci have been identified through linkage studies. Stuttering is highly variable regarding its phenotypes and molecular etiology. However, all stutters have some common features, including blocks in speech, prolongation, and repetition of sounds, syllables, and words. The involuntary actions associated with stuttering often involve increased eye blinking, tremors of the lips or jaws, head jerks, clenched fists, perspiration, and cardiovascular changes. In the present study, we recruited a consanguineous Pakistani family showing an autosomal recessive mode of inheritance. The exome sequencing identified a homozygous splice site variant in ARMC3 (Armadillo Repeat Containing 3) in a consanguineous Pashtun family of Pakistani origin as the underlying genetic cause of non-syndromic stuttering. The homozygous splice site variant (NM_173081.5:c.916 + 1G > A) segregated with the stuttering phenotype in this family. The splice change leading to the skipping of exon-8 is a loss of function (LoF) variant, which is predicted to undergo NMD (Nonsense mediated decay). Here, we report ARMC3 as a novel candidate gene causing the stuttering phenotype. ARMC3 may lead to neurodevelopmental disorders, including stuttering in humans.

Keywords: ARMC3; autosomal recessive; exome sequencing; splice site variant; stuttering.

Figure 1

Pedigree of the family showing the segregation of the ARMC3 variant in an autosomal recessive manner. Empty squares and circles show the unaffected males and females, respectively. The filled shapes show the affected individuals. The symbols labeled with asterisks show the individuals who participated in this study. Affected members (V-2 and V-4) showed a homozygous mutant genotype (A/A). Phenotypically unaffected individuals IV-3, IV-4, and V-1 were heterozygous (G/A), while V-3 showed the wild-type genotype (G/G).

Figure 2

(A) shows the cytogenic location of the ARMC3 gene on chromosome 10; (B) indicates the typical structure of ARMC3 containing 19 exons and the location of the ARMC3 variant by the red bar between the exons 8 and 9. (C) Chromatograms. (a) Affected individual, (b) carrier, and (c) unaffected control.

Figure 3

Superimposed 3D structures of wild-type and mutant ARMC3 proteins: (a) wild-type protein, (b) mutant protein, and (c) superimposed structure of wild-type and mutant proteins.

Figure 4

Molecular docking of the candidate proteins with the identified interactor: (a) docking of wild-type and (b) mutant ARMC3 proteins.