Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial personality. Clear knowledge of the circumscribed set of genes that are affected in Williams syndrome, along with the well-characterized neurobehavioural phenotype, offers the potential to elucidate neurogenetic principles that may apply in genetically and clinically more complex settings. The intraparietal sulcus, in the dorsal visual processing stream, has been shown to be structurally and functionally altered in Williams syndrome, providing a target for investigating resting-state functional connectivity and effects of specific genes hemideleted in Williams syndrome. Here, we tested for effects of the LIMK1 gene, deleted in Williams syndrome and important for neuronal maturation and migration, on intraparietal sulcus functional connectivity. We first defined a target brain phenotype by comparing intraparietal sulcus resting functional connectivity in individuals with Williams syndrome, in whom LIMK1 is hemideleted, with typically developing children. Then in two separate cohorts from the general population, we asked whether intraparietal sulcus functional connectivity patterns similar to those found in Williams syndrome were associated with sequence variation of the LIMK1 gene. Four independent between-group comparisons of resting-state functional MRI data (total n = 510) were performed: (i) 20 children with Williams syndrome compared to 20 age- and sex-matched typically developing children; (ii) a discovery cohort of 99 healthy adults stratified by LIMK1 haplotype; (iii) a replication cohort of 32 healthy adults also stratified by LIMK1 haplotype; and (iv) 339 healthy adolescent children stratified by LIMK1 haplotype. For between-group analyses, differences in intraparietal sulcus resting-state functional connectivity were calculated comparing children with Williams syndrome to matched typically developing children and comparing LIMK1 haplotype groups in each of the three general population cohorts separately. Consistent with the visuospatial construction impairment and hypersocial personality that typify Williams syndrome, the Williams syndrome cohort exhibited opposite patterns of intraparietal sulcus functional connectivity with visual processing regions and social processing regions: decreased circuit function in the former and increased circuit function in the latter. All three general population groups also showed LIMK1 haplotype-related differences in intraparietal sulcus functional connectivity localized to the fusiform gyrus, a visual processing region also identified in the Williams syndrome-typically developing comparison. These results suggest a neurogenetic mechanism, in part involving LIMK1, that may bias neural circuit function in both the general population and individuals with Williams syndrome.

中文翻译：

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威廉姆斯综合征半脱细胞和LIMK1变异都影响背流功能连接。

威廉姆斯综合征是一种罕见的遗传病，由半合子缺失导致影响7号染色体上的26个基因的约1.6 Mb半合子缺失（7q11.23），临床上具有两个认知/行为特征：相对于言语和非言语推理能力明显的视觉空间缺陷和超社会的人格。对威廉姆斯综合征中受限制的基因的明确了解以及充分表征的神经行为表型，提供了阐明可能适用于遗传和临床更复杂环境的神经遗传学原理的潜力。在威廉姆斯综合征中，背侧视觉处理流中的顶壁沟已在结构和功能上发生了改变，为研究静息状态功能连接性和威廉姆斯综合征中半删除的特定基因的作用提供了一个目标。在这里，我们测试了LIMK1基因对顶壁沟功能连通性的影响，该基因在威廉姆斯综合征中缺失，对于神经元的成熟和迁移很重要。我们首先通过比较具有典型发育中儿童的Williams综合征（其中LIMK1被半脱细胞）的个人的顶壁内沟静息功能连通性来定义目标脑表型。然后，在来自普通人群的两个独立队列中，我们询问与威廉姆斯综合征相似的顶壁沟内功能连接模式是否与LIMK1基因的序列变异相关。进行了四个独立的组间静息状态功能MRI数据比较（总n = 510）：（i）20名患有威廉姆斯综合征的儿童与20名年龄和性别相匹配的典型发育儿童进行比较；（ii）由LIMK1单倍型分层的99名健康成年人的发现队列；（iii）同样由LIMK1单倍型分层的32名健康成年人的复制队列；（iv）339名按LIMK1单倍型分层的健康青少年儿童。对于组间分析，计算比较了Williams综合征患儿与典型发育中的患儿并分别比较了三个普通人群中每一个的LIMK1单倍型组的顶壁内沟静息状态功能连接性的差异。与典型的Williams综合征的视觉空间构造障碍和超社会性格相一致，Williams综合征队列表现出与视觉加工区和社交加工区相反的顶壁内沟功能连通性模式：前者的回路功能降低而后者的回路功能提高。所有这三个普通人群也显示出LIMK1单倍体相关的差异，位于顶梭状回，位于视觉上的加工区域，也存在于威廉姆斯综合征（Williams syndrome）中，这是典型的发展性比较。这些结果表明，部分涉及LIMK1的神经遗传机制可能会使普通人群和Williams综合征患者的神经回路功能发生偏差。威廉姆斯综合症队列的顶壁沟功能连通性与视觉加工区和社交加工区呈现相反的模式：前者的回路功能降低而后者的回路功能提高。所有这三个普通人群也显示出LIMK1单倍体相关的差异，位于顶梭状回，位于视觉上的加工区域，也存在于威廉姆斯综合征（Williams syndrome）中，这是典型的发展性比较。这些结果表明，部分涉及LIMK1的神经遗传机制可能会使普通人群和Williams综合征患者的神经回路功能发生偏差。威廉姆斯综合症队列的顶壁沟功能连通性与视觉加工区和社交加工区呈现相反的模式：前者的回路功能降低而后者的回路功能提高。所有这三个普通人群也显示出LIMK1单倍体相关的差异，位于顶梭状回，位于视觉上的加工区域，也存在于威廉姆斯综合征（Williams syndrome）中，这是典型的发展性比较。这些结果表明，部分涉及LIMK1的神经遗传机制可能会使普通人群和Williams综合征患者的神经回路功能发生偏差。前者的电路功能降低，而后者的电路功能提高。所有这三个普通人群也显示出LIMK1单倍体相关的差异，位于顶梭状回，位于视觉上的加工区域，也存在于威廉姆斯综合征（Williams syndrome）中，这是典型的发展性比较。这些结果表明，部分涉及LIMK1的神经遗传机制可能会使普通人群和Williams综合征患者的神经回路功能发生偏差。前者的电路功能降低，而后者的电路功能提高。所有这三个普通人群也显示出LIMK1单倍体相关的差异，位于顶梭状回，位于视觉上的加工区域，也存在于威廉姆斯综合征（Williams syndrome）中，这是典型的发展性比较。这些结果表明，部分涉及LIMK1的神经遗传机制可能会使普通人群和Williams综合征患者的神经回路功能发生偏差。