Winters Lore, Van Hoof Evelien, De Catte Luc, Van Den Bogaert Kris, de Ravel Thomy, De Waele Liesbeth, Corveleyn Anniek, Breckpot Jeroen
Department of Pediatrics, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium.
Center for Human Genetics, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium.
Eur J Paediatr Neurol. 2017 Sep;21(5):745-753. doi: 10.1016/j.ejpn.2017.04.641. Epub 2017 Apr 26.
Fetal akinesia deformation sequence (FADS) or arthrogryposis multiplex congenita (AMC) is characterized by clinical ambiguity and genetic heterogeneity, hampering genetic diagnosis via traditional sequencing methods. Next generation sequencing (NGS) of all known disease-causing genes offers an elegant solution to identify the genetic etiology of AMC/FADS in a diagnostic setting.
An in-house developed disease-associated gene panel was conducted in two unrelated fetuses with FADS. First, a de novo analysis was performed on the entire disease-associated gene panel. If no pathogenic mutation was identified, analysis of variants retained in a specific subpanel with arthrogryposis/fetal akinesia-causing genes was performed.
In the first family, FADS relates to a homozygous c.484G > A (p.Glu162Lys) mutation in the gene RAPSN. The second case concerns a sporadic patient with brain anomalies and arthrogryposis due to a de novo hemizygous c.498C > T splice-site mutation in the pyruvate dehydrogenase-alpha 1 (PDHA1) gene.
NGS facilitated genetic diagnosis, and hence genetic counseling, for both families with AMC/FADS. Biallelic RAPSN mutations typically result in congenital myasthenia syndrome, or occasionally in FADS. This is the first report attributing the RAPSN mutation c.484G > A, identified in a homozygous state in patient 1, to FADS. The second patient represents the first case of AMC due to a PDHA1 mutation, advocating that pyruvate dehydrogenase deficiency should be considered in the differential diagnosis of fetal akinesia. This study illustrates the relevance of a disease-associated-gene panel as a diagnostic tool in pregnancies complicated by this genetically heterogeneous condition.
胎儿运动不能变形序列征（FADS）或先天性多发性关节挛缩症（AMC）具有临床诊断不明确和基因异质性的特点，这使得通过传统测序方法进行基因诊断受到阻碍。对所有已知致病基因进行下一代测序（NGS）为在诊断环境中确定AMC/FADS的遗传病因提供了一个很好的解决方案。
对两名患有FADS的无关胎儿进行了内部开发的疾病相关基因检测。首先，对整个疾病相关基因检测进行从头分析。如果未发现致病突变，则对保留在特定亚组中的具有关节挛缩/胎儿运动不能致病基因的变异进行分析。
在第一个家庭中，FADS与RAPSN基因中的纯合c.484G＞A（p.Glu162Lys）突变有关。第二例是一名散发患者，由于丙酮酸脱氢酶α1（PDHA1）基因的新生半合子c.498C＞T剪接位点突变，患有脑异常和关节挛缩症。
NGS有助于对两个患有AMC/FADS的家庭进行基因诊断，从而进行遗传咨询。双等位基因RAPSN突变通常导致先天性肌无力综合征，偶尔也会导致FADS。这是第一份将在患者1中以纯合状态鉴定的RAPSN突变c.484G＞A归因于FADS的报告。第二例患者代表了第一例由于PDHA1突变导致的AMC病例，这表明在胎儿运动不能的鉴别诊断中应考虑丙酮酸脱氢酶缺乏症。本研究说明了疾病相关基因检测作为诊断工具在患有这种基因异质性疾病的妊娠中的相关性。
