Contrasting neurofunctional correlates of face- and visuospatial-processing in children and adolescents with Williams syndrome: convergent results from four fMRI paradigms.

Understanding neurogenetic mechanisms underlying neuropsychiatric disorders such as schizophrenia and autism is complicated by their inherent clinical and genetic heterogeneity. Williams syndrome (WS), a rare neurodevelopmental condition in which both the genetic alteration (hemideletion of ~ twenty-six 7q11.23 genes) and the cognitive/behavioral profile are well-defined, offers an invaluable opportunity to delineate gene-brain-behavior relationships. People with WS are characterized by increased social drive, including particular interest in faces, together with hallmark difficulty in visuospatial processing. Prior work, primarily in adults with WS, has searched for neural correlates of these characteristics, with reports of altered fusiform gyrus function while viewing socioemotional stimuli such as faces, along with hypoactivation of the intraparietal sulcus during visuospatial processing. Here, we investigated neural function in children and adolescents with WS by using four separate fMRI paradigms, two that probe each of these two cognitive/behavioral domains. During the two visuospatial tasks, but not during the two face processing tasks, we found bilateral intraparietal sulcus hypoactivation in WS. In contrast, during both face processing tasks, but not during the visuospatial tasks, we found fusiform hyperactivation. These data not only demonstrate that previous findings in adults with WS are also present in childhood and adolescence, but also provide a clear example that genetic mechanisms can bias neural circuit function, thereby affecting behavioral traits.

Altered pubertal timing in 7q11.23 copy number variations and associated genetic mechanisms.

Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10-8, η2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10-5, ηp2 = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of STAG3L2 (p = 1.7x10-17), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with STAG3L2 and pituitary development as potential mediators.

Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome.

Genetic modifications leading to pain insensitivity phenotypes, while rare, provide invaluable insights into the molecular biology of pain and reveal targets for analgesic drugs. Pain insensitivity typically results from Mendelian loss-of-function mutations in genes expressed in nociceptive (pain-sensing) dorsal root ganglion (DRG) neurons that connect the body to the spinal cord. We document a pain insensitivity mechanism arising from gene overexpression in individuals with the rare 7q11.23 duplication syndrome (Dup7), who have 3 copies of the approximately 1.5-megabase Williams syndrome (WS) critical region. Based on parental accounts and pain ratings, people with Dup7, mainly children in this study, are pain insensitive following serious injury to skin, bones, teeth, or viscera. In contrast, diploid siblings (2 copies of the WS critical region) and individuals with WS (1 copy) show standard reactions to painful events. A converging series of human assessments and cross-species cell biological and transcriptomic studies identified 1 likely candidate in the WS critical region, STX1A, as underlying the pain insensitivity phenotype. STX1A codes for the synaptic vesicle fusion protein syntaxin1A. Excess syntaxin1A was demonstrated to compromise neuropeptide exocytosis from nociceptive DRG neurons. Taken together, these data indicate a mechanism for producing "genetic analgesia" in Dup7 and offer previously untargeted routes to pain control.

Dorsal visual stream and LIMK1: hemideletion, haplotype, and enduring effects in children with Williams syndrome.

BACKGROUND: Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed "hypersociability") and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS. METHODS: We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5-22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population. RESULTS: IPS structural (p < 10-4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, IPS gray matter volume (pdiscovery < 0.05 SVC, preplication = 0.0015) and imputed LIMK1 expression (pdiscovery = 10-15, preplication = 10-23) varied according to LIMK1 haplotype. CONCLUSIONS: This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.