Behav Genet DOI 10.1007/s10519-006-9090-7 ORIGINAL PAPER Speech Sound Disorder Influenced by a Locus in 15q14 Region Catherine M. Stein Æ Christopher Millard Æ Amy Kluge Æ Lara E. Miscimarra Æ Kevin C. Cartier Æ Lisa A. Freebairn Æ Amy J. Hansen Æ Lawrence D. Shriberg Æ H. Gerry Taylor Æ Barbara A. Lewis Æ Sudha K. Iyengar Received: 27 September 2005 / Accepted: 23 May 2006 Ó Springer Science+Business Media, Inc. 2006 Abstract Despite a growing body of evidence in- phonological memory, and that linkage at D15S118 was dicating that speech sound disorder (SSD) has an un- potentially influenced by a parent-of-origin effect derlying genetic etiology, researchers have not yet (LOD score increase from 0.97 to 2.17, P = 0.0633). identified specific genes predisposing to this condition. These results suggest shared genetic determinants in The speech and language deficits associated with SSD this chromosomal region for SSD, autism, and PWS/AS. are shared with several other disorders, including dys- lexia, autism, Prader-Willi Syndrome (PWS), and An- Keywords Phonology Æ Speech Æ Language Æ gelman’s Syndrome (AS), raising the possibility of gene Parent-of-origin Æ Allele-sharing sharing. Furthermore, we previously demonstrated that dyslexia and SSD share genetic susceptibility loci. The present study assesses the hypothesis that SSD also Introduction shares susceptibility loci with autism and PWS. To test this hypothesis, we examined linkage between SSD Speech–sound disorder (SSD) is a common communi- phenotypes and microsatellite markers on the chromo- cation disorder of unknown etiology with an estimated some 15q14–21 region, which has been associated with prevalence of 15.2% in children at age 3, persisting in autism, PWS/AS, and dyslexia. Using SSD as the phe- 3.8% of children by age 6 (Shriberg et al. 1999). The notype, we replicated linkage to the 15q14 region disorder is characterized by deficits in articulation, (P = 0.004). Further modeling revealed that this locus phonological processing, and in the cognitive repre- influenced oral-motor function, articulation and sentation of language. Although the causes of SSD have yet to be elucidated, a number of studies suggest that susceptibility to SSD is genetic, as previously de- Edited by Tatiana Faroud scribed (Stein et al. 2004). Prader-Willi syndrome (PWS) and Angelman syn- C. M. Stein Æ C. Millard Æ A. Kluge Æ L. E. Miscimarra Æ drome (AS), two well characterized disorders that are & K. C. Cartier Æ S. K. Iyengar ( ) influenced by loci in the 15q11–13 region with different Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building parent-of-origin effects (Dykens et al. 2004), are asso- Room 1315, 2103 Cornell Rd, Cleveland, OH 44106, USA ciated with speech disability (Lewis et al. 2002; Moncla e-mail: [email protected] et al. 1999). The majority of cases of PWS (70%) are the result of a deletion in the 15q11–q13 region, with L. A. Freebairn Æ A. J. Hansen Æ H. G. Taylor Æ B. A. Lewis Department of Pediatrics, Rainbow Babies & Childrens the remaining cases due to maternal uniparental di- Hospital, Case Western Reserve University, Cleveland, OH, somy. The deletion subtype of PWS is associated with USA articulation difficulties including poor oral motor skills (Cassidy et al. 1997), and lower scores in reading, vi- L. D. Shriberg Waisman Center, University of Wisconsin-Madison, sual processing, and communication (Butler et al. Madison, WI, USA 2004). Although individuals with PWS present with 123 Behav Genet depressed IQs (the average full scale IQ is 65), the SSD SSD are often co-morbid with language impairment associated with PWS is severe and not explained by IQ (LI). The comorbidity of SSD and LI has been esti- alone. In a study of 55 individuals with PWS (24 with mated at 6–21% for children with receptive language the deletion subtype), ranging in age from preschool to disorders, and 38–62% for children with expressive adult, all reported a history of or current enrollment in language disorders (Shriberg and Austin 1998). Thus, speech therapy for a SSD (Lewis et al. 2002). The comorbid expressive disorder is 2–3 times more com- deletion subtype of AS has also been associated with a mon in SSD than comorbid receptive disorder. Shri- lack of speech development and lower cognitive abili- berg et al. (1999) reported rates of co-morbidity ties (Moncla et al. 1999). In a survey of children with between SSD and LI in children with persistent speech AS (N = 20) all vocalized but only 10 acquired single delay of 11–15% at 6 years of age, with considerably words, with 15 words the maximum number acquired higher rates of 40–60% reported for preschool children (Alvares and Downing 1998). Most relied on non- (Shriberg and Austin 1998). Children with co-morbid speech methods of communication. Factors related to SSD and LI often present with reading disorders (RD) the expressive delay included cognitive delay as well as at school age. High rates of co-morbidity of LI with poor oral motor skills. A duplication of this region has RD have also been reported (Bishop 2001). Flax et al. been additionally associated with a phonological (2003) found that 68% of LI probands also met the awareness deficit, single word reading impairment, criteria for RD. articulation difficulties, language impairment, dyspr- Cognitive deficits shared by SSD and RD include axia, and motor impairment (Boyar et al. 2001). difficulties in the establishment of phonological, Linkage to the 15q11–q14 region has also been dem- semantic, and morphosyntactic representations and in onstrated for autism (reviewed in Muhle et al. 2004) cognitive processing (Stein et al. 2004). However, SSD (Fig. 1), another disorder involving communication differs from RD in two primary ways. First, whereas deficits, including speech and prosodic disorders reading is taught directly, speech acquisition is ac- (Shriberg et al. 2001). Although children with autism quired less directly through exposure to a language characteristically present with social language deficits, environment. Second, SSD can be diagnosed in chil- deficits in articulation including higher rates of residual dren of pre-school age, whereas RD cannot be diag- speech sound errors have been reported (Shriberg nosed until children have been exposed to reading et al. 2001). instruction. Many children with SSD eventually Fig. 1 Delineation of regions cM Our Markers Mb Associated Genes Linkage Autism (Nurmi et al 2003, Philipe 1999) of linkage to PWS, AS, 20 20 autism, and dyslexia for MPAI (20.6 Mb) chromosome 15q11–q21. The (Prader-Willi) width of the linkage interval GABRB3 (24.5 Mb) for each study is represented (autism) by a solid line flanked by two q11.2 diamonds. The reference q12 30 q13.1 30 scale for each study was q13.3 (32.58 cM) determined by aligning the D15S118 (33.9 Mb) markers used with the UCSC q14 q15.1 physical map. Genetic (cM) and physical (Mb) distances q21.1 D15S214 (38 Mb) Spelling (Nöthen et al 1999, Schülte-Körne 1998) q21.2 40 (41.98 cM) Phonemic coding efficiency (Chapman et al 2004) are not to scale 40 q21.3 Dyslexia (Morris et al 2000, Marino al, 2004) Single-word reading (Grigorenko et al 1997) D15S143 (45.9 Mb) (46.88 cM) Dyslexia (Nopola-Hemmi et al 2000) D15S126 (47 Mb) (48.08 cM) 50 50 (51.28 cM) D15S209 (51.5 Mb) EKN1 (53.6 Mb) (dyslexia) D15S117 (56.2 Mb) (56.38 cM) 60 60 123 Behav Genet develop deficits in reading, language, and spelling language, and reading skills (i.e., quantitative end- (Lewis et al. 2000). Pennington and colleagues have ophenotypes), in families ascertained through a pro- suggested that SSD predicts the development of dys- band with SSD. lexia in individuals from high-risk families (Raitano et al. 2004). This common etiology leads to the hypothesis that the two disorders share susceptibility Methods genes (Pennington 1997), and indeed, our previous genetic work supports this hypothesis (Stein et al. Study population 2004). Smith and colleagues (Smith et al. 1983) were the Children recruited as probands for the study were first to report linkage for dyslexia to chromosome 15. initially diagnosed as SSD by a speech–language Other evidence suggests linkage for dyslexia to the pathologist. Further criteria for SSD included re- chromosome 15q15–q21 region (DYX1; OMIM sponses on the Goldman–Fristoe Test of Articulation 127700) (Fig. 1; also reviewed in Fisher and DeFries (GFTA) below the 10th percentile and a minimum of 2002). Dyslexia-related endophenotypes have also four phonological process errors and severity rating of been linked to this region, including single-word 3–4 on the Khan–Lewis Phonological Analysis Test, an reading (Grigorenko et al. 1997), phonological aware- additional analysis of responses to the GFTA. The ness (Wigg et al. 2004), phonemic coding efficiency GFTA is standardized for children ages 2–16 years. (Chapman et al. 2004), and word identification Children were also required to have normal hearing, as (Chapman et al. 2004; Wigg et al. 2004). Spelling dis- demonstrated by passing a puretone audiometric ability has been linked to this region as well (No¨ then screening test; normal intelligence, defined as a per- et al. 1999; Schulte-Ko¨ rne et al. 1998; Wigg et al. formance IQ of at least 80 on the Wechsler Preschool 2004). However, other studies have not confirmed and Primary Scale of Intelligence-Revised (WPPSI-R) linkage for dyslexia or dyslexia endophenotypes to this or Wechsler Intelligence Scale for Children, 3rd Edi- region (Bisgaard et al. 1987; Cardon et al. 1994; Fisher tion (WISC-III); and a normal speech mechanism et al. 2002; Rabin et al. 1993).