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Abstract
BackgroundAutism 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.MethodsHere, 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 GPD2, 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.ResultscExN 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.ConclusionsWe 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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population
Phenotyping and genotyping of the multiplex family The multiplex autism spectrum disorder (ASD) pedigree selected for study (Fig. 1; Table 1) underwent clinical phenotyping and genotyping
The variant is in exon three of the GPD2 gene, within the region encoding the flavin adenine dinucleotide (FAD)-binding domain of the GPD2 protein (Additional file 2: Figure S1A)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies By definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. We are extremely limited in our ability to acquire or experimentally manipulate human brain tissue from living patients or post-mortem brain slices This has hampered efforts to study cellular and molecular abnormalities that accompany ASD, both during and after fetal and post-natal development. Both the relative integrity of brain structures in affected individuals and the diversity of ASD genetics suggest that convergent mechanisms that contribute to affectation in ASD may operate at the level of the cell [3, 4]. In vitro differentiation-based models of these neuronal cell types can identify cellular and molecular deficits associated with ASD and provide a tractable platform to screen for pharmacologic agents that can rescue these deficits
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