Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
Eur J Hum Genet. 2019 Oct;27(10):1611-1618. doi: 10.1038/s41431-019-0462-x. Epub 2019 Jul 5.
The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.
发育性和癫痫性脑病 (DEE) 是一组异质性的慢性脑病，常与神经元表达基因中的罕见新生非同义编码变异有关。在这里，我们描述了 8 名具有 DEE 表型的先证者，其特征包括智力障碍、癫痫和肌张力减退。外显子组 trio 分析显示，每个先证者的 TRPM3 基因均存在新生的杂合变异，该基因编码一种脑表达的瞬时受体电位通道。7 名先证者的 S4-S5 连接区均存在 TRPM3 重复的替代变异，p.(Val837Met)，该区域是一个保守结构域，在门控通道打开时被认为会发生构象变化。第 8 名个体为 TRPM3 柔性孔形成环和相邻的α-螺旋交界处的脯氨酸替代，p.(Pro937Gln)。TRPM3 中存在普遍的截断变异和微缺失，提示除了简单的杂合不足之外，还有其他的发病机制。我们得出结论，TRPM3 的新生变异是智力障碍和癫痫的原因。
