View-Revised (ADI-R) Were Used to Develop a Motor Potential Genes for Further Investigation
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J Neurodevelop Disord (2010) 2:210–223 DOI 10.1007/s11689-010-9063-2 Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci Judy F. Flax & Abby Hare & Marco A. Azaro & Veronica J. Vieland & Linda M. Brzustowicz Received: 19 May 2010 /Accepted: 10 September 2010 /Published online: 12 October 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Using behavioral and genetic information from gible verbal behaviors (NVMSD:ALL) and a related the Autism Genetics Resource Exchange (AGRE) data set phenotype restricted to individuals without significant we developed phenotypes and investigated linkage and comprehension difficulties (NVMSD:C). Using Affymetrix association for individuals with and without Autism 5.0 data, the PPL framework was employed to assess the Spectrum Disorders (ASD) who exhibit expressive lan- strength of evidence for or against trait-marker linkage and guage behaviors consistent with a motor speech disorder. linkage disequilibrium (LD) across the genome. Ingenuity Speech and language variables from Autism Diagnostic Pathway Analysis (IPA) was then utilized to identify Interview-Revised (ADI-R) were used to develop a motor potential genes for further investigation. We identified speech phenotype associated with non-verbal or unintelli- several linkage peaks based on two related language- speech phenotypes consistent with a potential motor speech Electronic supplementary material The online version of this article disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, (doi:10.1007/s11689-010-9063-2) contains supplementary material, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and which is available to authorized users. 4p15.2 and 21q22.2 for NVMSD:C. While no compelling J. F. Flax (*) evidence of association was obtained under those peaks, we Department of Genetics, Rutgers University, identified several potential genes of interest using IPA. 145 Bevier Road, Room 224, Conclusion: Several linkage peaks were identified based on Piscataway, NJ 08854, USA two motor speech phenotypes. In the absence of evidence e-mail: [email protected] of association under these peaks, we suggest genes for A. Hare further investigation based on their biological functions. Department of Genetics, Rutgers University, Given that autism spectrum disorders are complex with a 145 Bevier Road, Room 230A, wide range of behaviors and a large number of underlying Piscataway, NJ 08854, USA genes, these speech phenotypes may belong to a group of M. A. Azaro several that should be considered when developing narrow, Department of Genetics, Rutgers University, well-defined, phenotypes in the attempt to reduce genetic 145 Bevier Road, Room 226, heterogeneity. Piscataway, NJ 08854, USA V. J. Vieland Keywords Autism . Linkage analysis . Association Battelle Center for Mathematical Medicine, analysis . Motor Speech Disorder . Autism genes . Ingenuity ’ The Research Institute at Nationwide Children s Hospital Pathway Analysis (IPA) . PPL/PPLD and The Ohio State University, JW3921, 700 Children’s Drive, Columbus, OH 43205, USA Introduction L. M. Brzustowicz Department of Genetics, Rutgers University, 145 Bevier Road, Room 231, Over the past 10 years there has been compelling evidence Piscataway, NJ 08854, USA supporting a genetic basis for autism using a combination J Neurodevelop Disord (2010) 2:210–223 211 of behavioral family studies and genetic linkage and Speech and language in ASD association studies. However, these studies have produced results that are often inconsistent and sometimes contra- Speech and language impairments constitute a broadly dictory (Newbury et al. 2002). Some linkage studies have defined area. In their mildest forms they may be character- identified peaks based on the presence or absence of ized by a minor phonological or speech impairment that can autism or autism spectrum disorders (ASD), while other affect speech production and possibly reading ability. On studies have concentrated on more specific phenotypic and the more severe end of the language and speech continuum, clinical characterizations such as onset age of first words, a person might be unable to comprehend or process spoken family language history, sex of proband, obsessive language and/or be non-verbal or unintelligible. This vast compulsive and ritualistic behaviors, and social skills scope of speech and language disabilities seen in the ASD [(Alarcón et al. 2002; Auranen et al. 2003;Bradfordet population has been documented in detail (Rapin and Dunn al. 2001; Buxbaum et al. 2004;Liuetal.2008;Shaoetal. 2003; Tager-Flusberg et al. 2005). While some research 2003); See (Abrahams and Geschwind 2010) for a current supports the notion that there may be multiple relations linkage review]. among the language problems seen in SLI and autism, Of particular interest for several research groups has others feel that there is not enough evidence to support a been the attempt to define and then replicate significant genetic link (Lindgrin et al. 2009) and that ASD and SLI linkage signals using language-based phenotypes in ASD are distinctly different disorders that do not share the same probands with the objective of finding genes that are genes. associated with a specific language-related phenotype. Previous reports indicate that approximately 50% of all An area on chromosome 7 (q34–36) has been linked to children with autism never acquire functional language by both autism and expressive language impairments. A middle childhood (Bailey et al. 1996) while more current gene for a contactin associated protein, CNTNAP2,thatis estimates place this value as closer to 20% (Lord et al. downregulatedbyFOXP2andisknowntoinfluenceearly 2004). Yet little is known about why some individuals, brain development in humans, has been associated with despite years of intervention, never develop language while both ASD and language (Alarcón et al. 2008;Arkingetal. many others develop enough spoken language to commu- 2008;Vernesetal.2008). While chromosome 7q nicate at least minimally. Often the underlying cause is not continues to be an area of intense interest for both autism clear and may be presumed to be a social/interaction issue. and language, other linkage signals have been reported But what if language processing problems make incoming that are also based on language phenotypes in the ASD verbal information difficult or impossible to understand and population. Alarcón et al. (2005) reported linkage on severely limit verbal output? Conversely, what if problems chromosomes 3q and 17q using onset of first words and with speech output make speech very effortful, resulting in phrases as the behavioral phenotype while linkage on vocalizations that include only vowels sounds or verbal- chromosome 13q21 was reported by Bradford et al. (2001) izations that are unintelligible to those around them, as in for ASD probands and family members with a history of the case of childhood apraxia of speech (CAS)? language-related problems. Bartlett et al. (2004) identified CAS is a motor speech disorder that involves poor motor linkage in the same region for a sample of families with a planning and results in speech output with compromised history of Specific Language Impairment (SLI) without intelligibility ranging from its most severe form of ASD. SLI is a failure to develop language normally expressive language production, which is characterized by without explanatory factors such as low IQ, gross very limited consonant production, to full phrase produc- neurological impairment, or inadequate environment. tion with multiple omissions, substitutions, distortions, and They suggest that although SLI and ASD are distinctly reversals of speech sounds. While good epidemiologic data different disorders, both are genetically complex and may on the prevalence of CAS is lacking, population estimates share specific susceptibility genes or variants of genes. derived from referral data suggest that approximately one to Spence et al. (2006) stratified expressive language two children per 1,000 are affected with CAS (Shriberg et characteristics into word and phrase speech delay in al. 1997). There has been limited study of CAS in terms of ASD probands and family members in an attempt to its genetic origins, however, in their family and genetic better define the language endophenotype and reduce studies of speech sound disorders, Lewis et al. (2004) phenotypic heterogeneity. They found evidence for link- looked at a small sample of children with a diagnosis of age in several already identified locations supporting the CAS and reported that 59% had at least one parent with idea that more discretely defined characteristics of ASD, some type of speech sound disorder. Moreover, in 86% of specifically language endophenotypes, may improve lo- the families, at least one nuclear family member reported calization of linkage signals and strengthen existing either a speech sound disorder or a language disorder. In a findings. recent related study of speech sound disorders Lewis et al. 212 J Neurodevelop Disord (2010) 2:210–223 (2007) report that 36 of 147 (24%) of parents of children phenotype common to autism but also potentially common with speech sound disorders also report similar problems as to other speech and language disorders. children. Very little has been reported about individuals with Motor speech phenotypes autism whose vocalizations are effortful, unintelligible, or non-existent.