Identification of a Microdeletion at the 7q33-q35 Disrupting the CNTNAP2 Gene in a Brazilian Stuttering Case

Speech and language disorders are some of the most common referral reasons to child development centers accounting for approximately 40% of cases. Stuttering is a disorder in which involuntary repetition, prolongation, or cessation of the sound precludes the flow of speech. About 5% of individuals in the general population have a stuttering problem, and about 80% of the affected children recover naturally. The causal factors of stuttering remain uncertain in most cases; studies suggest that genetic factors are responsible for 70% of the variance in liability for stuttering, whereas the remaining 30% is due to environmental effects supporting a complex cause of the disorder. The use of high-resolution genome wide array comparative genomic hybridization has proven to be a powerful strategy to narrow down candidate regions for complex disorders. We report on a case with a complex set of speech and language difficulties including stuttering who presented with a 10Mb deletion of chromosome region 7q33-35 causing the deletion of several genes and the disruption of CNTNAP2 by deleting the first three exons of the gene. CNTNAP2 is known to be involved in the cause of language and speech disorders and autism spectrum disorder and is in the same pathway as FOXP2, another important language gene, which makes it a candidate gene for causal studies speech and language disorders such as stuttering. (C) 2010 Wiley-Liss, Inc.

Polimorfismos dos genes ADA e CNTNAP2 em indivíduos com Transtornos do Espectro do Autismo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering

A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p = 0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p = 0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI. Published by Elsevier Inc.

Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects

Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3, ROBO1, DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case–control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families.