Rett syndrome (RTT) is a severe neurodevelopmental disorder reported worldwide in diverse populations. RTT is diagnosed primarily in females, with clinical findings manifesting early in life. Despite the variable rates across populations, RTT has an estimated prevalence of ∼1 in 10,000 live female births. Among 215 Saudi Arabian patients with neurodevelopmental and autism spectrum disorders, we identified 33 patients with RTT who were subsequently examined by genome-wide transcriptome and mitochondrial genome variations. To the best of our knowledge, this is the first in-depth molecular and multiomics analyses of a large cohort of Saudi RTT cases with a view to informing the underlying mechanisms of this disease that impact many patients and families worldwide. The patients were unrelated, except for 2 affected sisters, and comprised of 25 classic and eight atypical RTT cases. The cases were screened for methyl-CpG binding protein 2 (MECP2), CDKL5, FOXG1, NTNG1, and mitochondrial DNA (mtDNA) variants, as well as copy number variations (CNVs) using a genome-wide experimental strategy. We found that 15 patients (13 classic and two atypical RTT) have MECP2 mutations, 2 of which were novel variants. Two patients had novel FOXG1 and CDKL5 variants (both atypical RTT). Whole mtDNA sequencing of the patients who were MECP2 negative revealed two novel mtDNA variants in two classic RTT patients. Importantly, the whole-transcriptome analysis of our RTT patients' blood and further comparison with previous expression profiling of brain tissue from patients with RTT revealed 77 significantly dysregulated genes. The gene ontology and interaction network analysis indicated potentially critical roles of MAPK9, NDUFA5, ATR, SMARCA5, RPL23, SRSF3, and mitochondrial dysfunction, oxidative stress response and MAPK signaling pathways in the pathogenesis of RTT genes. This study expands our knowledge on RTT disease networks and pathways as well as presents novel mutations and mtDNA alterations in RTT in a population sample that was not previously studied.

中文翻译：

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Rett综合征，神经发育障碍，全转录组和线粒体基因组多组学分析确定了新的变异和疾病途径。

Rett综合征（RTT）是一种严重的神经发育障碍，全世界范围内都有报道。RTT主要在女性中诊断，临床发现表现为生命早期。尽管各个人群之间的比率各不相同，但RTT在10,000例活产女婴中的估计患病率约为1。在215名具有神经发育和自闭症谱系障碍的沙特阿拉伯患者中，我们确定了33例RTT患者，随后对其进行了全基因组转录组和线粒体基因组变异检查。据我们所知，这是首次对一大批沙特RTT病例进行深入的分子和多组学分析，目的是了解这种疾病的潜在机制，该机制影响全球许多患者和家庭。除2个受影响的姐妹外，其余患者均无关。包括25个经典案例和8个非典型RTT案例。使用全基因组实验策略筛选了甲基CpG结合蛋白2（MECP2），CDKL5，FOXG1，NTNG1和线粒体DNA（mtDNA）变体，以及拷贝数变异（CNV）。我们发现15例患者（13例经典和2例非典型RTT）具有MECP2突变，其中2例是新型变异。两名患者患有新型FOXG1和CDKL5变异体（均为非典型RTT）。MECP2阴性患者的完整mtDNA测序揭示了两名经典RTT患者中的两个新mtDNA变异体。重要的是，我们的RTT患者血液的全转录组分析以及与RTT患者脑组织先前表达谱的进一步比较显示77个显着失调的基因。基因本体论和相互作用网络分析表明，MAPK9，NDUFA5，ATR，SMARCA5，RPL23，SRSF3和线粒体功能障碍，氧化应激反应和MAPK信号通路在RTT基因的发病机理中具有潜在的关键作用。这项研究扩展了我们对RTT疾病网络和途径的认识，并提出了以前未研究过的人群样本中RTT中的新突变和mtDNA改变。