Section on Integrative Neuroimaging, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
J Neurodev Disord. 2023 Aug 26;15(1):29. doi: 10.1186/s11689-023-09493-x.
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.
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.
IPS structural (p < 10 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 (p < 0.05 SVC, p = 0.0015) and imputed LIMK1 expression (p = 10, p = 10) varied according to LIMK1 haplotype.
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.
威廉姆斯综合征（WS）是一种罕见的神经发育障碍，由染色体 7q11.23 上约 25 个基因的单倍体缺失引起，为研究明确的遗传异常与明确的神经行为特征之间的关联提供了极好的机会。临床上，WS 的特征是社交驱动力增加（通常称为“过度社交”）和严重的视空间构建缺陷。先前的研究将 WS 中的视空间问题与背侧视觉处理流的改变联系起来。我们研究了 LIMK1 的单倍体缺失和单倍型变异对半侧缺失和单侧缺失对背侧流（特别是内顶叶沟[IPS]）的结构和功能的影响，该基因在 WS 患者中半侧缺失，并与神经元成熟和迁移有关，而 IPS 是已知在 WS 成人中改变的区域。
我们使用纵向 MRI 在一个 5-22 岁的 WS 儿童发展队列中（33 名参与者的 76 次就诊，280 次就诊于 94 名年龄和性别匹配的典型发育参与者）测试 IPS 的结构和功能变化。我们还对 7q11.23 上存在罕见较短半侧缺失的 12 名个体进行了 MRI 研究，这些个体均包括 LIMK1。最后，我们测试了 LIMK1 变异对 IPS 结构的影响，并在两个来自普通人群的健康个体的独立队列中对 LIMK1 表达进行了推断。
先前在成人中报道的 IPS 结构（校正后 p < 10 FDR）和功能（校正后 p <.05 FDR）异常在 WS 儿童中得到了证实，并且与持久的遗传机制一致，从幼儿期到成年期均保持稳定。在短半侧缺失队列中，发现了与 WS 相似的 IPS 缺陷，尽管在结构和功能发现方面，其效应大小均小于 WS。最后，在按 LIMK1 单倍型分层的两个普通人群队列中的每一个队列中，IPS 灰质体积（校正后 p < 0.05 SVC，p = 0.0015）和推断的 LIMK1 表达（p = 10，p = 10）根据 LIMK1 单倍型而变化。
这项工作提供了对导致 WS 表型的神经生物学和遗传机制的深入了解，并且更普遍地提供了一个引人注目的例子，说明遗传变异如何通过对神经中介物的分子影响来影响人类认知，并且在某些情况下导致神经认知障碍。
