1Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110 USA.
2Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110 USA.
Mol Autism. 2019 Dec 30;10:51. doi: 10.1186/s13229-019-0306-0. eCollection 2019.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk.
Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in , a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted.
cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes.
We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.
自闭症谱系障碍（ASD）是一种神经发育障碍，在普通人群中具有明显的遗传性。这在很大程度上归因于多基因易感性的影响，遗传易感性在表型表达上表现出明显的性别差异。在人类细胞系统中模拟 ASD 的尝试主要涉及与 ASD 表型相似的罕见新生突变。然而，根据定义，这些模型不能代表多基因易感性，多基因易感性占人群归因风险的绝大部分。
在这里，我们进行了我们所知的首次尝试，使用在表现出遗传易感性递增程度表型的患者衍生诱导多能干细胞（iPSC）对多发性自闭症进行建模（缺失、中度、严重）。这些家庭成员共享一个以前与发育障碍相关但本身不足以导致 ASD 的基因中的不确定意义变异（VUS）。来自三个一级亲属和一个无关对照的 iPSC 被分化为皮质兴奋性（cExN）和皮质抑制性（cIN）神经元，并进行了细胞表型和转录组分析。
与来自未受影响的相关和无关个体的神经球相比，来自两个受影响个体的 cExN 神经球的大小减小。这种减小至少部分归因于受影响个体的细胞在开始 cExN 神经诱导时凋亡增加。同样，与未受影响的个体相比，受影响个体的 cIN 神经祖细胞的凋亡增加。对 cExN 和 cIN 神经祖细胞的转录组分析显示，与受影响有关的分子特征，包括与神经发育、神经元功能和行为相关的基因套件的失调，以及与 ASD 风险相关基因的表达改变。
我们从一个多例自闭症家族的细胞模型分析中提供了 ASD 多基因易感性的形态、生理和转录组学特征的证据。ASD 通常是基于累加遗传易感性遗传的。因此，确定多基因和单基因易感性导致的趋同细胞和分子表型可能为确定罕见高度有害突变的不同影响哪些也可能适用于常见自闭症综合征提供关键桥梁。
