Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mol Autism. 2020 Oct 6;11(1):75. doi: 10.1186/s13229-020-00382-x.
Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs).
We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns.
Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs.
The RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD.
ASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.
从头变异和隐性遗传变异都与自闭症谱系障碍（ASD）有关。本研究旨在使用外显子组数据对常染色体上具有双等位基因遗传变异或男性 X 连锁遗传变异的隐性遗传基因（RIGs）进行优先级排序，并研究 RIGs 与具有新生变异（DNGs）的基因之间的功能关系。
我们使用生物信息学管道分析了来自西蒙斯单倍型收集的 1799 个 ASD 四重奏（包含一个先证者、一个无病同胞和他们的父母）的全外显子组测序数据，并对常染色体上罕见的双等位基因遗传变异或男性 X 连锁遗传变异的候选 RIGs 进行优先级排序。基于不同的遗传视角，包括遗传变异、功能网络和大脑表达模式，对 RIGs 和 DNGs 之间的关系进行了表征。
在大脑中表达的双等位基因或半合子约束基因中，ASD 先证者携带的常染色体上的双等位基因遗传蛋白截断变异（PTV）（p=0.038）和男性 X 连锁遗传 PTV 明显多于无病同胞。我们确定了 8 个常染色体和 13 个 X 连锁候选 RIGs，其中包括 11 个与神经发育障碍相关的基因。总共在 1799 个先证者中的 26 个（1.4%）检测到这些 21 个候选 RIGs 的双等位基因遗传变异或 X 连锁遗传变异。然后我们整合了之前报道的 ASD 中的已知或候选基因，最终获得了 70 个 RIGs 和 87 个 DNGs 进行分析。我们发现，与 DNGs 携带多个新生变异相比，RIGs 携带多个隐性遗传变异的可能性较低。此外，RIGs 和 DNGs 显著共表达并相互作用，形成了一个富含已知功能 ASD 簇的网络，尽管与 DNGs 相比，RIGs 不太可能富集在这些功能簇中。此外，尽管 RIGs 和 DNGs 在人类大脑中表现出相似的表达模式，但 RIGs 与产前大脑区域、中间皮质层和兴奋性神经元的关联程度低于 DNGs。
本研究分析的 RIGs 需要功能验证，结果需要在更多的 ASD 患者中进行复制。
ASD RIGs 在功能上与 DNGs 相关，但与 DNGs 相比，它们表现出更高的异质性。
