Over the past 10 years there has been compelling evidence supporting a genetic basis for autism using a combination of behavioral family studies and genetic linkage and association studies. However, these studies have produced results that are often inconsistent and sometimes contradictory (Newbury et al. 2002
). Some linkage studies have identified peaks based on the presence or absence of autism or autism spectrum disorders (ASD), while other studies have concentrated on more specific phenotypic and clinical characterizations such as onset age of first words, family language history, sex of proband, obsessive compulsive and ritualistic behaviors, and social skills [(Alarcón et al. 2002
; Auranen et al. 2003
; Bradford et al. 2001
; Buxbaum et al. 2004
; Liu et al. 2008
; Shao et al. 2003
); See (Abrahams and Geschwind 2010
) for a current linkage review].
Of particular interest for several research groups has been the attempt to define and then replicate significant linkage signals using language-based phenotypes in ASD probands with the objective of finding genes that are associated with a specific language-related phenotype. An area on chromosome 7 (q34–36) has been linked to both autism and expressive language impairments. A gene for a contactin associated protein, CNTNAP2
, that is down regulated by FOXP2 and is known to influence early brain development in humans, has been associated with both ASD and language (Alarcón et al. 2008
; Arking et al. 2008
; Vernes et al. 2008
). While chromosome 7q continues to be an area of intense interest for both autism and language, other linkage signals have been reported that are also based on language phenotypes in the ASD population. Alarcón et al. (2005
) reported linkage on chromosomes 3q and 17q using onset of first words and phrases as the behavioral phenotype while linkage on chromosome 13q21 was reported by Bradford et al. (2001
) for ASD probands and family members with a history of language-related problems. Bartlett et al. (2004
) identified linkage in the same region for a sample of families with a history of Specific Language Impairment (SLI) without ASD. SLI is a failure to develop language normally without explanatory factors such as low IQ, gross neurological impairment, or inadequate environment. They suggest that although SLI and ASD are distinctly different disorders, both are genetically complex and may share specific susceptibility genes or variants of genes. Spence et al. (2006
) stratified expressive language characteristics into word and phrase speech delay in ASD probands and family members in an attempt to better define the language endophenotype and reduce phenotypic heterogeneity. They found evidence for linkage in several already identified locations supporting the idea that more discretely defined characteristics of ASD, specifically language endophenotypes, may improve localization of linkage signals and strengthen existing findings.
Speech and language in ASD
Speech and language impairments constitute a broadly defined area. In their mildest forms they may be characterized by a minor phonological or speech impairment that can affect speech production and possibly reading ability. On the more severe end of the language and speech continuum, a person might be unable to comprehend or process spoken language and/or be non-verbal or unintelligible. This vast scope of speech and language disabilities seen in the ASD population has been documented in detail (Rapin and Dunn 2003
; Tager-Flusberg et al. 2005
). While some research supports the notion that there may be multiple relations among the language problems seen in SLI and autism, others feel that there is not enough evidence to support a genetic link (Lindgrin et al. 2009
) and that ASD and SLI are distinctly different disorders that do not share the same genes.
Previous reports indicate that approximately 50% of all children with autism never acquire functional language by middle childhood (Bailey et al. 1996
) while more current estimates place this value as closer to 20% (Lord et al. 2004
). Yet little is known about why some individuals, despite years of intervention, never develop language while many others develop enough spoken language to communicate at least minimally. Often the underlying cause is not clear and may be presumed to be a social/interaction issue. But what if language processing problems make incoming verbal information difficult or impossible to understand and severely limit verbal output? Conversely, what if problems with speech output make speech very effortful, resulting in vocalizations that include only vowels sounds or verbalizations that are unintelligible to those around them, as in the case of childhood apraxia of speech (CAS)?
CAS is a motor speech disorder that involves poor motor planning and results in speech output with compromised intelligibility ranging from its most severe form of expressive language production, which is characterized by very limited consonant production, to full phrase production with multiple omissions, substitutions, distortions, and reversals of speech sounds. While good epidemiologic data on the prevalence of CAS is lacking, population estimates derived from referral data suggest that approximately one to two children per 1,000 are affected with CAS (Shriberg et al. 1997
). There has been limited study of CAS in terms of its genetic origins, however, in their family and genetic studies of speech sound disorders, Lewis et al. (2004
) looked at a small sample of children with a diagnosis of CAS and reported that 59% had at least one parent with some type of speech sound disorder. Moreover, in 86% of the families, at least one nuclear family member reported either a speech sound disorder or a language disorder. In a recent related study of speech sound disorders Lewis et al. (2007
) report that 36 of 147 (24%) of parents of children with speech sound disorders also report similar problems as children.
Very little has been reported about individuals with autism whose vocalizations are effortful, unintelligible, or non-existent. One of the few studies (Gernsbacher et al. 2009
) was a retrospective study of children’s oral-motor skills that compared toddlers with autism to matched controls. Using videotapes and a detailed questionnaire, they determined that the quality of oral motor skills during the early years was associated with the level of speech intelligibility of the individuals with autism in later years. Minimally verbal older children had poorer oral motor skills as toddlers.
In the current Autism Genetic Resource Exchange (AGRE) dataset, approximately 16% of the individuals who were evaluated with the Autism Diagnostic Interview-Revised (ADI-R) (Lord et al. 1994
; Rutter et al. 2003
) are non-verbal or minimally verbal at the time of their evaluations. Another 16% of the individuals in the dataset have speech that is unintelligible to most people.
Based on our review of the speech and language characteristics of the subjects in the AGRE database, we suggest that there is a subset of individuals with and without ASD who exhibit an expressive language problem that ranges from being non-verbal to having expressive language that is unintelligible to others and may actually be described as a severe motor speech disorder such as verbal apraxia. As these speech and language behaviors are seen in only a subset of individuals with autism but also seen in individuals who do not meet ASD criteria, we investigated linkage and association for this behavior as part of a broader phenotype.