Abstract：
BACKGROUND: Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile -an episignature.
OBJECTIVE: We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing.
METHODS: Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature.
RESULTS: WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3.
CONCLUSIONS: Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS\'s in the KDM6A gene.
OBJECTIVE: We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing.
METHODS: Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature.
RESULTS: WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3.
CONCLUSIONS: Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS\'s in the KDM6A gene.
摘要：
背景：高胰岛素血症性低血糖（HI）可能是歌舞uki综合征（KS）的表现特征，这是由KMT2D或KDM6A中的功能丧失变体引起的。由于这些基因在维持染色质的甲基化状态中起着关键作用，具有致病变异的个体具有疾病特异性的表观基因组谱-表观特征.
目的：我们评估了三个在基因检测时表现为新生儿发病HI而没有典型KS特征的个体中发现的三个新的部分KDM6A重复的致病性。
方法：通过HI的常规靶向下一代测序鉴定了三个不同的部分KDM6A重复，并最初分类为具有不确定意义的变体（VUS）作为其位置，因此它们对基因的影响，不知道。进行全基因组测序(WGS)以利用在两个个体中进行的DNA甲基化谱分析来定位重复的断点,以研究KS特异性表标签的存在。
结果：WGS证实先证者1中的重复是致病性的，因为它导致基因正常拷贝的移码，导致提前终止密码子。先证者2和3中确定的重复没有改变阅读框，因此在WGS之后它们的重要性仍然不确定。随后的DNA甲基化谱分析在先证者2中但在先证者3中没有鉴定出KS特异性表特征。
结论：我们的发现证实了KDM6A部分基因重复在KS病因中的作用，并强调了进行深入的分子遗传学分析以正确评估VUS在KDM6A基因中的临床意义的重要性。
目的：我们评估了三个在基因检测时表现为新生儿发病HI而没有典型KS特征的个体中发现的三个新的部分KDM6A重复的致病性。
方法：通过HI的常规靶向下一代测序鉴定了三个不同的部分KDM6A重复，并最初分类为具有不确定意义的变体（VUS）作为其位置，因此它们对基因的影响，不知道。进行全基因组测序(WGS)以利用在两个个体中进行的DNA甲基化谱分析来定位重复的断点,以研究KS特异性表标签的存在。
结果：WGS证实先证者1中的重复是致病性的，因为它导致基因正常拷贝的移码，导致提前终止密码子。先证者2和3中确定的重复没有改变阅读框，因此在WGS之后它们的重要性仍然不确定。随后的DNA甲基化谱分析在先证者2中但在先证者3中没有鉴定出KS特异性表特征。
结论：我们的发现证实了KDM6A部分基因重复在KS病因中的作用，并强调了进行深入的分子遗传学分析以正确评估VUS在KDM6A基因中的临床意义的重要性。
