Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing
Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing
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DOI：
10.1136/jmedgenet-2018-105775
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发表时间：
2019-06-01
影响因子：
4
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Iwama, Kazuhiro;Mizuguchi, Takeshi;Matsumoto, Naomichi
Rett综合征（RTT）是一种特征性神经系统疾病，表现为神经发育里程碑的退行性丧失。典型的RTT通常由甲基- cpg结合蛋白2 （MECP2）异常引起。我们的目的是利用全外显子组测序（WES）研究mecp2阴性典型/非典型RTT和RTT样表型的遗传景观。方法对77例mecp2阴性的典型RTT （n=11）、非典型RTT （n=22）或不符合RTT标准的RTT样表型（n=44）患者进行WES检查。结果77例患者中有39例（50.6%）存在28个已知基因的致病性或可能致病性单核苷酸变异。基于wes的CNV分析显示，77例患者中有8例（10.4%）存在6个已知基因（包括MECP2）的致病性缺失。总的来说，77例患者的诊断率为47例（61.0%）。此外，在四个新基因中发现了强候选变异：转运V0亚基A1的AT Pase H+ (ATP6V0A1)、泛素特异性肽酶8 （USP8）和微管相关丝氨酸/苏氨酸激酶3 （MAST3）的每个新变异，以及核受体辅抑制因子2 （NCOR2）的双等位变异。我们的研究提供了一个新的景观，包括额外的遗传变异，有助于rtt样表型，突出了综合遗传分析的重要性。
Background Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).Methods We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.Results Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of AT Pase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2).Conclusions Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.