Human Genetics and Cognitive Functions, Institut Pasteur, CNRS UMR3571, Institut Universitaire de France, Université Paris Cité, Paris, France; email:
Department of Child and Adolescent Psychiatry, University Hospital of the Goethe University, Frankfurt am Main, Germany.
Annu Rev Genet. 2024 Nov;58(1):487-512. doi: 10.1146/annurev-genet-111523-102614.
Autism represents a large spectrum of diverse individuals with varying underlying genetic architectures and needs. For some individuals, a single de novo or ultrarare genetic variant has a large effect on the intensity of specific dimensions of the phenotype, while, for others, a combination of thousands of variants commonly found in the general population are involved. The variants with large impact are found in up to 30% of autistic individuals presenting with intellectual disability, significant speech delay, motor delay, and/or seizures. The common variants are shared with those found in individuals with attention-deficit/hyperactivity disorder, major depressive disorders, greater educational attainment, and higher cognitive performance, suggesting overlapping genetic architectures. The genetic variants modulate the function of chromatin remodeling and synaptic proteins that influence the connectivity of neuronal circuits and, in interaction with the environment of each individual, the subsequent cognitive and personal trajectory of the child. Overall, this genetic heterogeneity mirrors the phenotypic diversity of autistic individuals and provides a helpful bridge between biomedical and neurodiversity perspectives. We propose that participative and multidisciplinary research should use this information to understand better the assessment, treatments, and accommodations that individuals with autism and families need.
自闭症代表了一大群具有不同潜在遗传结构和需求的个体。对于一些个体来说，单一的新生或超罕见遗传变异对表型的特定维度的强度有很大影响，而对于其他个体来说，涉及到数千种常见于普通人群的变异。在表现出智力障碍、严重言语延迟、运动延迟和/或癫痫的自闭症个体中，高达 30%的个体中发现了具有较大影响的变异。常见的变异与注意力缺陷多动障碍、重度抑郁症、更高的教育程度和更高的认知表现的个体中发现的变异共享，这表明存在重叠的遗传结构。遗传变异调节染色质重塑和突触蛋白的功能，这些蛋白影响神经元回路的连接性，并且与每个个体的环境相互作用，影响儿童随后的认知和个人轨迹。总的来说，这种遗传异质性反映了自闭症个体的表型多样性，并为生物医学和神经多样性视角之间提供了一个有用的桥梁。我们提出，参与式和多学科研究应该利用这些信息来更好地理解自闭症个体和家庭所需的评估、治疗和适应。
