Abstract：
Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.
We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.
A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.
We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.
We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.
A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.
We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.
摘要：
目的：Witteveen-Kolk综合征（WITKOS）是一种罕见的，由SIN3A基因杂合功能缺失改变引起的常染色体显性神经发育障碍。WITKOS具有可变的表达能力，通常与其他神经发育障碍重叠。在这项研究中,我们表征了一个独特的DNA甲基化表观遗传特征(表观特征),将WITKOS与未受影响的个体以及具有表观特征的其他神经发育障碍个体区分开来,并描述了9例先前未发表的SIN3A单倍体功能不全个体.
方法：我们研究了20例SIN3A杂合改变的个体外周血样本的表型特征和全基因组DNA甲基化。共有14个样本用于鉴定表观特征和建立预测性诊断生物标志物。而诊断模型用于研究其余6个样本的甲基化模式。
结果：鉴定出WITKOS特异性的主要低甲基化DNA甲基化谱，并且分类器模型能够诊断以前未解析的测试用例。表观特征足够灵敏以检测具有不同程度的表型严重性的携带SIN3A单倍体不足变体的个体。
结论：我们确定了一部小说，由于SIN3A单倍体不足，WITKOS中的鲁棒表观标记。这种表观特征有可能帮助识别和诊断患有WITKOS的个体。
方法：我们研究了20例SIN3A杂合改变的个体外周血样本的表型特征和全基因组DNA甲基化。共有14个样本用于鉴定表观特征和建立预测性诊断生物标志物。而诊断模型用于研究其余6个样本的甲基化模式。
结果：鉴定出WITKOS特异性的主要低甲基化DNA甲基化谱，并且分类器模型能够诊断以前未解析的测试用例。表观特征足够灵敏以检测具有不同程度的表型严重性的携带SIN3A单倍体不足变体的个体。
结论：我们确定了一部小说，由于SIN3A单倍体不足，WITKOS中的鲁棒表观标记。这种表观特征有可能帮助识别和诊断患有WITKOS的个体。
