The genomic and clinical landscape of fetal akinesia
The genomic and clinical landscape of fetal akinesia
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DOI：
10.1038/s41436-019-0680-1
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发表时间：
2020-03-01
影响因子：
8.8
通讯作者：
Cirak, Sebahattin
中科院分区：
文献类型：
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作者：
Pergande, Matthias;Motameny, Susanne;Cirak, Sebahattin
目的胎儿运动障碍具有多种临床亚型，有160多种基因相关，但遗传病因尚不完全清楚。方法采用新一代测序（NGS）技术，对来自47个无亲缘关系家庭的51例患者进行分析，旨在破解胎儿运动障碍（FA）的基因组图谱。结果在37例病例中鉴定出可能的致病基因变异，并报告了41例新的变异。此外，我们报告了8例推定的致病变异，其中包括9例新的变异。我们的工作确定了14种新的胎儿运动障碍疾病基因关联：ADSSL1、ASAH1、ASPM、ATP2B3、EARS2、FBLN1、PRG4、PRICKLE1、ROR2、SETBP1、SCN5A、SCN8A和ZEB2。此外，一对兄弟姐妹携带TNNT1的纯合拷贝数变异，TNNT1是一种罕见的先天性肌病基因，通过基因本体分析与关节挛缩有关。结论我们的分析表明，导致原发性骨骼肌疾病的遗传缺陷可能未被充分诊断，特别是RYR1的致病变异。我们讨论了三个新的假定的胎儿运动障碍基因：GCN1， IQSEC3和RYR3。其中，IQSEC3和RYR3最近被认为是神经肌肉疾病相关基因，我们的研究结果支持它们作为FA候选基因。通过将NGS与深度临床表型相结合，我们获得了73%的成功率。
Purpose Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. Methods In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). Results We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. Conclusion Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.