Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.
School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.
Clin Genet. 2023 May;103(5):553-559. doi: 10.1111/cge.14311. Epub 2023 Feb 27.
EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.
EMC1 编码内质网（ER）膜蛋白复合物（EMC）的亚基 1，是一种参与膜蛋白生物合成的跨膜结构域插入酶。EMC1 的变体被描述为导致全身发育迟缓、张力减退、皮质视觉障碍以及通常在 MRI 扫描上出现脑萎缩的原因。我们报告了一名个体，其表现为严重的全身发育迟缓和进行性小脑萎缩，外显子组测序发现 EMC1 内含子 3 中的杂合性必需剪接位点变异（NM_015047.3：c.287-1G>A）。全基因组测序（WGS）在 EMC1 的内含子 20 中发现了一个深内含子变异（NM_015047.3：c.2588-771C>G），该变异通过计算机程序预测会导致 pre-mRNA 剪接受到破坏，但预测效果不佳。逆转录-PCR（RT-PCR）显示与 c.2588-771C>G 变异相关的假外显子的随机激活以及源自 c.287-1G>A 变异的错误剪接。该病例突出了 WGS 和 RNA 研究在识别和评估深内含子变异的可能致病性方面的作用，并扩展了 EMC1 相关疾病的基因型和表型谱。
