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Abstract：
Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.
摘要：
肠和膀胱蠕动异常的内脏肌病包括巨细胞-微结肠肠蠕动综合征和慢性肠假性梗阻的临床谱。绝大多数病例是由ACTG2中的显性变异引起的；然而，内脏肌病的整体遗传结构尚未得到很好的表征.我们确定了53个家庭，基于巨膀胱的内脏肌病，功能性膀胱/胃肠道梗阻,或微结肠。使用靶向ACTG2测序和外显子组测序的组合。我们报告的分子诊断率为64%(34/53)，其中97%（33/34）归因于ACTG2。引人注目的是，涉及CpG二核苷酸的五个保守精氨酸残基中的错义突变占队列疾病的49％（26/53）。作为一个群体,ACTG2阴性病例具有更有利的临床结局和更受限制的疾病.在ACTG2阳性组中，不良结局(以完全肠外营养依赖为特征，死亡,或移植）总是由于精氨酸错义等位基因之一。特定残基的分析表明p.Arg178>p.Arg257>p.Arg40以及其他较少报道的站点p.Arg63和p.Arg211。这些结果为ACTG2相关疾病提供了基因型-表型相关性，并证明了精氨酸错义变化在内脏肌病中的重要性。
