Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays

Abstract

Genetic contributions to human cognition and behavior are clear but difficult to define. Williams syndrome (WS) provides a unique model for relating single genes to visual-spatial cognition and social behavior. We defined a approximately 1.5 Mb region of approximately 25 genes deleted in >98% of typical WS and then rare small deletions, showing that visual-spatial construction (VSC) in WS was associated with the genes GTF2IRD1 and GTF2I. To distinguish the roles of GTF2IRD1 and GTF2I in VSC and social behavior, we utilized multiple genomic methods (custom high resolution oligonucleotide microarray, multicolor FISH and somatic cell hybrids analyzed by PCR) to identify individuals deleted for either gene but not both. We analyzed genetic, cognitive and social behavior in a unique individual with WS features (heart defects, small size, facies), but with an atypical deletion of a set of genes that includes GTF2IRD1, but not GTF2I. The centromeric breakpoint localized to the region 72.32-72.38 Mb and the telomeric breakpoint to 72.66 Mb, 10 kb downstream of GTF2IRD1. Cognitive testing (WPPSI-R, K-BIT, and PLS-3) demonstrated striking deficits in VSC (Block Design, Object Assembly) but overall performance 1.5-3 SD above WS means. We have now integrated the genetic, clinical and cognitive data with previous reports of social behavior in this subject. These results combine with previous data from small deletions to suggest the gene GTF2IRD1 is associated with WS facies and VSC, and that GTF2I may contribute to WS social behaviors including increased gaze and attention to strangers.

FIG. 1

Facial photographs of Subject 5889 at 14 months (A), 2.6 years (B) and 7 years (C) old. Reproduced with parental permission.

FIG. 2

Deletion breakpoint analysis of Subject 5889. A: Physical map of BAC/PAC/cosmid probes used for molecular cytogenetics with fluorescence in situ hybridization (FISH) and summary of results defining deletion in 5889; B: Polymerase chain reaction (PCR) with somatic cell hybrids of the distal breakpoint region identified by FISH; C: High resolution array CGH analysis of a 14 megabase region on chromosome 7 (64-77Mb) using a custom isothermal oligonucleotide tiling array. The top panel shows the complete tiled region in a 10X window averaged view (200bp probe spacing). Bottom left and right panels show zoomed in views of the proximal and distal breakpoints for the deletion in which all data points (unaveraged data set with 385,013 probes and 20bp median spacing) were analyzed. Red line segments in both bottom panels denote copy number calls by the analysis algorithm (see Materials and Methods).

FIG. 3

Molecular map of the Subject 5889. High resolution molecular determination of deletion breakpoints in Subject 5889 occur within 72.32-72.38Mb at centromeric end and and 10 kb downstream of GTF2IRD1 at telomeric end.

FIG. 4

Subject 5889's scores on cognitive measures (WPPSI-R, K-BIT and PLS-3) as compared to mean WS performance (upper panel, Typical WS score denoted by right arrow) and compared to WS children with typical deletion (hatched bars) and typically developed children (lower panel, Normal score denoted by right arrow).

FIG. 5

Quantification of social behavior in Subject 5889 versus WS, Down syndrome (DS) and controls (typically developed, TD). Data replotted from Doyle et al., 2004 and Järvinen-Pasley et al., 2008. A: The atypical social behavior of Subject 5889 was reflected in parental ratings of social behavior using the SISQ at age 2.55 [Doyle et al., 2004, versus WS only] and were repeated at age 4.6 years [Järvinen-Pasley et al., 2008 versus a single typical WS case only]. In contrast with age-matched typical WS group, as well as children with DS and TD, the parental ratings (converted to z-scores for comparison) revealed that 5889's Global Sociability and Approach Strangers scores both at 2.55 years (z = -2.59 and -2.39, respectively) and at 4.86 years (z = -2.6 and -3.2), were significantly different from her peers in the typical WS group. B: A number of key differences in direct social behavior were noted between the Subject 5889 and children with typical WS deletions [shown in Järvinen-Pasley et al., 2008], relative to control children with DS for the mean total durations of three ethogram behaviors. Overall, WS children with full deletions were significantly less likely than children with DS to spend time far away in proximity from (p=.007), and to engage in non-social activities with (p=.01), with adults, whether familiars (mothers) or novel (the experimenter), highlighting their tendency toward social over non-social activities. Furthermore, WS children with full deletions were significantly more likely to maintain eye contact with the novel adult than did children with DS (p=.038). Compared to the typical WS group, Subject 5889 (tested at age 2.5y) spent greater amount of time far away in proximity from the novel adult (z = 7.96), and engaged in non-social activities for greater amount of time with both the parent (z = 2.39) and the novel adult (z = 6.00). The difference in the amount of eye contact toward the unfamiliar adult failed to reach significance (z = 1.24), due to a large SD within the WS group. These results provide converging evidence for the SISQ data presented above, showing that Subject 5889 did not display the hypersociability characteristic of individuals with WS full deletions.

FIG. 5

Quantification of social behavior in Subject 5889 versus WS, Down syndrome (DS) and controls (typically developed, TD). Data replotted from Doyle et al., 2004 and Järvinen-Pasley et al., 2008. A: The atypical social behavior of Subject 5889 was reflected in parental ratings of social behavior using the SISQ at age 2.55 [Doyle et al., 2004, versus WS only] and were repeated at age 4.6 years [Järvinen-Pasley et al., 2008 versus a single typical WS case only]. In contrast with age-matched typical WS group, as well as children with DS and TD, the parental ratings (converted to z-scores for comparison) revealed that 5889's Global Sociability and Approach Strangers scores both at 2.55 years (z = -2.59 and -2.39, respectively) and at 4.86 years (z = -2.6 and -3.2), were significantly different from her peers in the typical WS group. B: A number of key differences in direct social behavior were noted between the Subject 5889 and children with typical WS deletions [shown in Järvinen-Pasley et al., 2008], relative to control children with DS for the mean total durations of three ethogram behaviors. Overall, WS children with full deletions were significantly less likely than children with DS to spend time far away in proximity from (p=.007), and to engage in non-social activities with (p=.01), with adults, whether familiars (mothers) or novel (the experimenter), highlighting their tendency toward social over non-social activities. Furthermore, WS children with full deletions were significantly more likely to maintain eye contact with the novel adult than did children with DS (p=.038). Compared to the typical WS group, Subject 5889 (tested at age 2.5y) spent greater amount of time far away in proximity from the novel adult (z = 7.96), and engaged in non-social activities for greater amount of time with both the parent (z = 2.39) and the novel adult (z = 6.00). The difference in the amount of eye contact toward the unfamiliar adult failed to reach significance (z = 1.24), due to a large SD within the WS group. These results provide converging evidence for the SISQ data presented above, showing that Subject 5889 did not display the hypersociability characteristic of individuals with WS full deletions.

FIG. 6

WS Cognition: Gene Map of Visual-Spatial Construction and Social Behavior. A: Summary of facial features, cognition test scores, and gene copy number analysis of GTF2IRD1 for WS patients with typical and atypical (AT) deletions. B: WS region gene map and deletion summary of typical and atypical WS patients and corresponding mapping of reported phenotypes.

FIG. 6

WS Cognition: Gene Map of Visual-Spatial Construction and Social Behavior. A: Summary of facial features, cognition test scores, and gene copy number analysis of GTF2IRD1 for WS patients with typical and atypical (AT) deletions. B: WS region gene map and deletion summary of typical and atypical WS patients and corresponding mapping of reported phenotypes.