Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6,Clinical Genetics

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Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-02-20 , DOI: 10.1111/cge.13691
Emanuele Agolini ₁ , Claudio Cherchi ₂ , Emanuele Bellacchio ₃ , Diego Martinelli ₄ , Dario Cocciadiferro ₁ , Renato Cutrera ₂ , Maria B Chiarini Testa ₂ , Chiara Barone ₅ , Sebastiano Bianca ₅ , Antonio Novelli ₁

Affiliation

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.

中文翻译：

扩大与ADCY6双等位基因变异相关的致命性先天性挛缩综合征8的临床和分子谱

多发性先天性关节病（AMC）被定义为由于胎儿活动性降低而在两个以上关节和多个身体区域发生的先天性非渐进性挛缩。迄今为止，已经鉴定出400多个AMC致病基因。一些分离的AMC表型是由于编码运动神经元结构，功能和髓鞘形成所需成分的基因中的突变而产生的，例如在ADCY6编码6型腺苷酸环化酶的情况下，由于双等位基因变体，ADCY6失活已经存在与致命的先天性挛缩综合征8（LCCS8）相关。迄今为止，仅报道了来自两个家庭的四名LCCS8患者。在这里，我们描述了一个新的患者，该患者受到严重形式的AMC的影响，其中包含两个新的化合物杂合子ADCY6。我们的发现扩展了LCCS8的临床和突变谱，显示了迄今为止报道的ADCY6错义变体的影响（通过分子建模预测）与表型的严重性之间可能存在相关性。

更新日期：2020-03-26

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