A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy.
A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy.
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DOI：
10.1002/mgg3.352
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发表时间：
2018-03
影响因子：
2
通讯作者：
Vedam R
中科院分区：
文献类型：
--
作者：
Geetha TS;Lingappa L;Jain AR;Govindan H;Mandloi N;Murugan S;Gupta R;Vedam R
有几个基因与精神发育迟滞的高度可变表现有关。EMC 1基因的突变最近有报道。在此，我们描述了一个近亲婚姻所生的先证者，他表现为早期婴儿型癫痫、舟状头畸形、发育迟缓、中枢性肌张力减退、肌肉萎缩和严重的小脑和脑干萎缩。先证者的基因检测使用定制临床外显子组和靶向下一代测序进行。随后通过桑格测序对亲本中的变体进行分离分析，并通过RNA测序对剪接变体进行评价。临床外显子组测序鉴定了EMC 1基因中的一种新型纯合内含子剪接变体（chr 1：19564510 C>T，c.1212 + 1G>A，NM_015047. 2）。无论是人口数据库（ExAC和1000个基因组）还是我们的内部数据库（n = 1,500）都没有报告这种罕见的变异，预计会影响剪接。先证者的RNA测序数据证实了内含子11保留的异常剪接，从而在所得mRNA中引入了终止密码子。预计这种无义突变会导致蛋白质合成提前终止，从而导致EMC 1蛋白功能丧失。我们报告，第一次异常EMC 1 RNA剪接作为疾病发病机制的潜在原因的作用。我们研究中观察到的严重癫痫扩大了疾病相关表型，也强调了对内含子剪接突变进行全面筛查的必要性。
Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy. Genetic testing in the proband was performed using custom clinical exome and targeted next‐generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing. Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein. We report, for the first time the role of aberrant EMC1 RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease‐associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations.
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影响因子：
11.1
作者：
Janer A;Prudent J;Paupe V;Fahiminiya S;Majewski J;Sgarioto N;Des Rosiers C;Forest A;Lin ZY;Gingras AC;Mitchell G;McBride HM;Shoubridge EA
通讯作者：
Shoubridge EA
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
9.8
作者：
Harel, Tamar;Yesil, Gozde;Lupski, James R.
通讯作者：
Lupski, James R.
影响因子：
4.8
作者：
Wang, Fan;Song, Wensi;Segatori, Laura
通讯作者：
Segatori, Laura
DOI：
10.1093/bioinformatics/btp698
发表时间：
2010-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Li H;Durbin R
通讯作者：
Durbin R