Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene
Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene
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Rett 和 Rett 样综合征：将遗传谱扩展到 KIF1A 和 GRIN1 基因
DOI：
10.1002/mgg3.968
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发表时间：
2019-09-11
影响因子：
2
通讯作者：
Bao, Xinhua
中科院分区：
文献类型：
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作者：
Wang, Jiaping;Zhang, Qingping;Bao, Xinhua
本研究旨在探讨Rett综合征（RTT）或Rett样表型的新遗传病因。方法对44例中国RTT或RTT样表型患者进行靶向下一代测序（NGS），其中MECP2、CDKL5和FOXG1基因分析为阴性。结果检出率为31.8%（14/44）。在一名具有典型RTT所有核心特征的女孩中发现了KIF1A的一种全新致病变异（c.275_276ins AA, p. Cys92*）。1例非典型RTT患者被检出有新的GRIN1致病变异（c.2337C > A, p. Val793Phe）。此外，在一名女孩中检测到PPT1基因的复合杂合致病性变异体，该女孩最初表现出典型的RTT特征，但随后发展为神经性ceroid脂褐病（NCL）。在我们的队列中也发现了KCNQ2、MEF2C、WDR45、TCF4、IQSEC2和SDHA的致病变异。结论这是首次将GRIN1和KIF1A的致病变异与RTT和rett样基因联系起来。我们的研究结果扩大了中国RTT或Rett样患者的遗传异质性，也提示一些遗传代谢性疾病（如NCL）患者最初可能表现出Rett特征，临床随访对诊断至关重要。
Background This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes. Methods Targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative. Results The detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort. Conclusions It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett-like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett-like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow-up is essential for the diagnosis.