The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.
The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.
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DOI：
10.1038/s41436-019-0639-2
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Milewicz DM
中科院分区：
文献类型：
--
作者：
Pinard A;Guey S;Guo D;Cecchi AC;Kharas N;Wallace S;Regalado ES;Hostetler EM;Sharrief AZ;Bergametti F;Kossorotoff M;Hervé D;Kraemer M;Bamshad MJ;Nickerson DA;Smith ER;Tournier-Lasserve E;Milewicz DM
烟雾病血管病（MMA）是一种以大动脉闭塞为特征的脑血管疾病，可导致儿童期开始的中风。12个改变的基因易患MMA，但大多数欧洲血统的病例没有确定的遗传触发因素。分析了来自39个三聚体的外显子组测序。我们在三个以前与MMA无关的基因中发现了四种从头变异：CHD4，hocT3和SETD5。在158个无关的MMA先证者中鉴定出这些基因中的其他罕见变异，进一步支持了CHD 4和hocT3中的罕见致病变异易患MMA。以前的研究发现，这些基因在患有发育障碍（DD）、智力残疾和先天性心脏病的儿童中存在新生变异。这些基因编码参与染色质重塑的蛋白质，并与先前报道的导致MMA样脑血管闭塞性疾病的基因（YY1AP 1，SMARCAL 1）一起，暗示染色质重塑被破坏是诱发早发性大动脉闭塞性脑血管疾病的分子途径。此外，这些数据扩展了由于CHD 4、hocT3和SET D5改变而导致的表型多效性谱，超出DD至脑血管动脉中的晚发型疾病，并强调需要评估与DD相关的基因的临床并发症至成年。
Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. Exome sequencing from 39 trios were analyzed. We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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