Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders

Supernumerary sex chromosome aneuploidies (referred to here as X/Y-aneuploidies), the presence of extra X- and/or Y-chromosomes, occur at a collective rate of ~1/475 births (Nielsen & Wohlert, 1990). Sex chromosome trisomies (e.g., XXX, XXY, XYY) occur most frequently, each with rates of ~1/900 births, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are considerably rarer, each with rates of ~1/85,000 births or fewer (Linden, Bender, & Robinson, 1995). There is longstanding evidence that children with X/Y-aneuploidies have language-learning difficulties. However, only recently, attention also has been drawn to social difficulties, including autism spectrum disorder (ASD) symptomatology, in these groups (for reviews, see Leggett, Jacobs, Nation, Scerif, & Bishop, 2010; Lee, Lopez, Adeyemi, & Giedd, 2011). Given the close connection between idiopathic language impairments and ASDs and the fact no prior studies have examined language and/or social functioning in children with the X/Y tri-, tetra-, and pentasomies, the current study sought to examine both of these domains of functioning in a sample of children with XXX, XXXX, XXXXX, XYY, XXY, XXXY, and XXXXY and typically developing (TD) controls. In particular, we aimed to evaluate dosage effects of X- and Y-chromosomes on language and social functioning in order to shed light not only on the nature of language and social difficulties in children with X/Y aneuploidies, but also on the possible contributions of the X- and Y-chromosomes to idiopathic language impairments and ASDs. Prospective newborn screening studies of X/Y-aneuploidies (Walzer, Bashir, & Silbert, 1990; Ratcliffe et al., 1982, Bender et al., 1983; Netley & Rovet, 1982) and more recent reports (Bishop et al., 2011; Ross, Zeger, Kushner, Zinn, & Roeltgen, 2009) have noted increased rates of language-based learning disorders, including speech, semantic and syntactic deficits (which we refer to as ‘structural language’ or non-social language deficits) and depressed Verbal IQ scores in XXY and XXX. While these children often have lower nonverbal IQ scores than siblings, significant nonverbal learning difficulties are not commonly reported (Bender, Linden, & Robinson, 1991). For males with an additional Y-chromosome (XYY), cognitive findings are inconsistent. Some prospective studies reported about a one standard deviation decrease in general cognitive functioning (Ratcliffe et al., 1982; Walzer et al., 1990). However, when data were pooled across early studies, no significant depression in overall cognitive abilities was found (Netley, 1986). Nevertheless, more recent research suggests that at a minimum, males with XYY have depressed verbal cognitive and structural language skills relative to TD peers (Bishop et al., 2011; Ross et al., 2009). Research on children with X-chromosome tetra- and pentasomies (XXXX, XXXXX, XXXY, XXXXY) suggests decreases in verbal and nonverbal intellectual abilities with each additional X-chromosome (Linden et al., 1995), such that many of these individuals have cognitive abilities in the borderline to intellectually disabled range (Visootsak, Rosner, Dykens, Tartaglia, & Graham, 2007; though Gropman et al., 2010 suggests that nonverbal cognition is relatively preserved in XXXXY despite profound language deficits). Furthermore, studies suggest significant structural language impairments in these groups (Visootsak et al., 2007), including severe dyspraxia resulting in limited to no speech in XXXXY (Gropman et al., 2010). In summary, there appears to be strong evidence for structural language impairments in X/Y-aneuploidies. However, less is known about pragmatic or more social aspects of language, including discourse, understanding of metaphor and humor, and nonverbal communication. The few studies that have been completed converge in implicating pragmatic language difficulties in X/Y trisomies using standardized (Ross et al., 2009) and experimental cognitive tasks (van Rijn et al., 2007) as well as parent report (Bishop et al., 2011). However, no study has examined pragmatic language skills in X/Y tetra- and pentasomies, or pragmatic language vis-a-vis structural language functioning in any X/Y-aneuploidy. Even less is known about the social phenotype associated with X/Y-aneuploidies. Recent studies suggest that the addition of one X-chromosome in males (XXY) is associated with heightened rates of ASDs and social-cognitive impairments (Bishop et al., 2011; Bruining, Swaab, Kas, & van Engeland, 2009; van Rijn, Swaab, Aleman, & Kahn, 2006). In contrast, reports of females with XXX and males with XXXY and XXXXY are not indicative of increased ASD risk (Bishop et al., 2011; Visootsak et al., 2007). Reports of males with XYY indicate that an additional Y-chromosome may be associated with social difficulties, as these males appear to have increased rates of ASDs and ASD symptomatology (Bishop et al., 2011; Geerts, Steyaert, & Fryns, 2003). Thus, the current research sought to examine verbal and nonverbal intellectual skills, structural and pragmatic language abilities, and ASD symptomatology in a large sample of children with sex chromosome tri-, tetra-, and pentasomies and TD controls in order to examine X- and Y-chromosome dosage effects on these phenotypes. Unlike previous studies investigating genotype-specific profiles, we focused on quantity of supernumerary sex chromosomes. Therefore, we collapsed across genotypes (e.g., +0X=XX, XY; +1X=XXX, XXY), and in the case of tetra- and pentasomies, limited sample size necessitated combining these groups (i.e., +2/3X=XXXX, XXXXX, XXXY, XXXXY; consistent with prior work by Visootsak et al., 2007) in order to answer study questions regarding X and Y dosage effects. We predict that: 1- Increased X- and Y-chromosome number will be associated with increased intellectual impairments with a discrepantly stronger impact on verbal relative to nonverbal intelligence. 2-Supernumerary X- and Y-chromosomes will be associated with impairments in both structural and pragmatic language; however, a supernumerary Y-chromosome will be associated with more pronounced pragmatic than structural language deficits. 3-Elevated ASD symptomatology will be associated with X/Y-aneuploidy, but supernumerary X-chromosome dosage effects will not be present.