Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6
Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6
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DOI：
10.1111/cge.13691
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发表时间：
2020-02-20
影响因子：
3.5
通讯作者：
Novelli, Antonio
中科院分区：
文献类型：
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作者：
Agolini, Emanuele;Cherchi, Claudio;Novelli, Antonio
先天性多发性关节挛缩症（AMC）是指由于胎儿活动度降低而导致的两个以上关节和多个身体部位的先天性非进行性挛缩。到目前为止，已经确定了400多个AMC的致病基因。一些孤立的AMC表型是由于编码运动神经元结构、功能和髓鞘形成所需组分的基因突变而出现的，如编码腺苷酸环化酶6型的ADCY6的情况。由于双等位基因变体，ADCY6失活先前已与致死性先天性挛缩综合征8（LCCS 8）相关。到目前为止，只有来自两个家庭的四名LCCS 8患者被报告。在这里，我们描述了一个新的病人受到严重形式的AMC，窝藏两个新的复合杂合变异ADCY6。我们的研究结果扩展了LCCS 8的临床和突变谱，表明迄今为止报道的ADCY6错义变体的影响（通过分子建模预测）与表型的严重程度之间可能存在相关性。
Arthrogryposis multiplex congenita (AMC) is defined as congenital, non-progressive contractures in more than two joints and in multiple body areas, resulting from reduced fetal mobility. So far, more than 400 causative genes for AMC have been identified. Some isolated AMC phenotypes arise as a result of mutations in genes encoding components required for motor neuron structure, function, and myelination, as in the case of ADCY6 encoding the enzyme adenylyl cyclase type 6. ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8). So far, only four LCCS8 patients, from two families, have been reported. Here, we describe a new patient affected by a severe form of AMC, harboring two novel compound heterozygous variants in ADCY6. Our findings expand the clinical and mutational spectrum of LCCS8, showing a possible correlation between the impact of the ADCY6 missense variants reported to date, predicted by molecular modeling, and the severity of the phenotype.