Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada.
BC Children's Hospital, Vancouver, BC V5Z 4H4, Canada.
Genes (Basel). 2021 Jul 8;12(7):1053. doi: 10.3390/genes12071053.
Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (, , , , and ). All are shared among the three children, except , which is only present in the most severely affected child. The compound heterozygous variants in and the maternally inherited variant in are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. is also involved in synapse functions, and and are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.
自闭症谱系障碍（ASD）是儿童中最常见的神经发育障碍，具有很高的遗传性。然而，在多病例家庭中，遗传变异如何导致 ASD 仍不清楚。我们对一个有三个受影响孩子的家庭进行全基因组测序（WGS），发现了 ASD 相关基因和途径中的多个遗传 DNA 变异（、、、、和）。所有这些变异都在三个孩子中共享，除了仅存在于最严重受影响孩子中的，其为复合杂合变异。和中的母系遗传变异被认为是这个家庭中 ASD 的主要危险因素。这两个基因都参与神经元活动，包括突触功能和 GABA 能神经传递系统，这些都与 ASD 的发病机制高度相关。也参与突触功能，和则参与染色质组织。我们的数据表明，多个遗传罕见变异，每个变异的影响都具有亚阈值和/或可变性，可能会汇聚到某些途径，并在数量上和累加性上发挥作用，或者通过二次打击或多次打击作用于 ASD 的发病机制。此外，这种多次打击模型进一步支持了 ASD 发展的复杂遗传、多因素病因的数量性状假说。
