Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
Genes (Basel). 2021 Oct 26;12(11):1699. doi: 10.3390/genes12111699.
Autism spectrum disorder (ASD) is a genetically heterogenous neurodevelopmental disorder. In the early years of next-generation sequencing, de novo germline variants were shown to contribute to ASD risk. These germline mutations are present in all of the cells of an affected individual and can be detected in any tissue, including clinically accessible DNA sources such as blood or saliva. In recent years, studies have also implicated de novo somatic variants in ASD risk. These somatic mutations arise postzygotically and are present in only a subset of the cells of an affected individual. Depending on the developmental time and progenitor cell in which a somatic mutation occurs, it may be detectable in some tissues and not in others. Somatic mutations detectable at relatively low sequencing coverage in clinically accessible tissues are suggested to contribute to 3-5% of simplex ASD diagnoses, and "brain limited" somatic mutations have been identified in postmortem ASD brain tissue. Somatic mutations likely represent the genetic diagnosis in a proportion of otherwise unexplained individuals with ASD, and brain limited somatic mutations can be used as markers to discover risk genes, cell types, brain regions, and cellular pathways important for ASD pathogenesis and to potentially target for therapeutics.
自闭症谱系障碍（ASD）是一种遗传异质性的神经发育障碍。在下一代测序的早期，新生种系变异被证明会增加 ASD 的风险。这些种系突变存在于受影响个体的所有细胞中，可在任何组织中检测到，包括临床可及的 DNA 来源，如血液或唾液。近年来，研究还表明新生体突变与 ASD 风险相关。这些体细胞突变是合子后发生的，仅存在于受影响个体的一部分细胞中。根据体细胞突变发生的时间和祖细胞的不同，它可能在某些组织中可检测到，而在其他组织中不可检测到。在临床上可及的组织中，以相对较低的测序覆盖度检测到的体细胞突变，被认为可导致 3-5%的单纯 ASD 诊断，并且在死后 ASD 脑组织中已鉴定出“大脑受限”的体细胞突变。体细胞突变可能代表了一部分 ASD 患者的遗传诊断，而大脑受限的体细胞突变可用作标记物，以发现 ASD 发病机制中重要的风险基因、细胞类型、脑区和细胞途径，并可能成为治疗的靶点。
