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Novel ACTG2 variants disclose allelic heterogeneity and bi‐allelic inheritance in pediatric chronic intestinal pseudo‐obstruction
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-12-08 , DOI: 10.1111/cge.13895 Ivana Matera 1 , Domenico Bordo 2 , Marco Di Duca 3 , Margherita Lerone 3 , Giuseppe Santamaria 1 , Marta Pongiglione 4 , Antonella Lezo 5 , Antonella Diamanti 6 , Maria Immacolata Spagnuolo 7 , Alessio Pini Prato 8 , Daniele Alberti 9 , Girolamo Mattioli 10 , Paolo Gandullia 11 , Isabella Ceccherini 1
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-12-08 , DOI: 10.1111/cge.13895 Ivana Matera 1 , Domenico Bordo 2 , Marco Di Duca 3 , Margherita Lerone 3 , Giuseppe Santamaria 1 , Marta Pongiglione 4 , Antonella Lezo 5 , Antonella Diamanti 6 , Maria Immacolata Spagnuolo 7 , Alessio Pini Prato 8 , Daniele Alberti 9 , Girolamo Mattioli 10 , Paolo Gandullia 11 , Isabella Ceccherini 1
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Variants in the ACTG2 gene, encoding a protein crucial for correct enteric muscle contraction, have been found in patients affected with chronic intestinal pseudo‐obstruction, either congenital or late‐onset visceral myopathy, and megacystis‐microcolon‐intestinal hypoperistalsis syndrome. Here we report about ten pediatric and one adult patients, from nine families, carrying ACTG2 variants: four show novel still unpublished missense variants, including one that is apparently transmitted according to a recessive mode of inheritance. Four of the remaining five probands carry variants affecting arginine residues, that have already been associated with a severe phenotype. A de novo occurrence of the variants could be confirmed in six of these families. Since a genotype–phenotype correlation is affected by extrinsic factors, such as, diagnosis delay, quality of clinical management, and intra‐familial variability, we have undertaken 3D molecular modeling to get further insights into the effects of the variants here described. The present findings and further ACTG2 testing of patients presenting with intestinal pseudo‐obstruction, will improve our understanding of visceral myopathies, including implications in the prognosis and genetic counseling of this set of severe disorders.
中文翻译：
新型ACTG2变体揭示了儿童慢性假性肠梗阻的等位基因异质性和双等位基因遗传
在患有慢性假性肠梗阻（先天性或迟发性内脏肌病）和巨囊-小结肠-肠蠕动减退综合征的患者中发现了ACTG2基因的变异，该基因编码一种对正确肠肌收缩至关重要的蛋白质。在这里，我们报告了来自 9 个家庭的 10 名儿科患者和 1 名成年患者携带ACTG2变异：四个显示出尚未发表的新错义变异，其中一个显然是根据隐性遗传模式传播的。其余 5 个先证者中有 4 个携带影响精氨酸残基的变异，这些变异已经与严重的表型相关。一个从头可以在其中六个家族中确认变异的发生。由于基因型-表型相关性受外在因素的影响，例如诊断延迟、临床管理质量和家族内变异性，我们进行了 3D 分子建模，以进一步了解此处描述的变异的影响。目前的发现和对假性肠梗阻患者的进一步ACTG2检测将提高我们对内脏肌病的理解，包括对这组严重疾病的预后和遗传咨询的影响。
更新日期：2021-02-08
中文翻译：
新型ACTG2变体揭示了儿童慢性假性肠梗阻的等位基因异质性和双等位基因遗传
在患有慢性假性肠梗阻（先天性或迟发性内脏肌病）和巨囊-小结肠-肠蠕动减退综合征的患者中发现了ACTG2基因的变异，该基因编码一种对正确肠肌收缩至关重要的蛋白质。在这里，我们报告了来自 9 个家庭的 10 名儿科患者和 1 名成年患者携带ACTG2变异：四个显示出尚未发表的新错义变异，其中一个显然是根据隐性遗传模式传播的。其余 5 个先证者中有 4 个携带影响精氨酸残基的变异，这些变异已经与严重的表型相关。一个从头可以在其中六个家族中确认变异的发生。由于基因型-表型相关性受外在因素的影响，例如诊断延迟、临床管理质量和家族内变异性，我们进行了 3D 分子建模，以进一步了解此处描述的变异的影响。目前的发现和对假性肠梗阻患者的进一步ACTG2检测将提高我们对内脏肌病的理解，包括对这组严重疾病的预后和遗传咨询的影响。
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