Männistö Jonna M E, Hopkins Jasmin J, Hewat Thomas I, Nasser Fatima, Burrage Joseph, Dastamani Antonia, Mirante Alice, Murphy Nuala, Rzasa Jessica, Kerkhof Jennifer, Relator Raissa, Johnson Matthew B, Laver Thomas W, Weymouth Luke, Houghton Jayne A L, Wakeling Matthew N, Sadikovic Bekim, Dempster Emma L, Flanagan Sarah E
Department of Clinical and Biomedical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
Kuopio Pediatric Research Unit, Faculty of Health Sciences, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
J Clin Endocrinol Metab. 2025 Apr 22;110(5):e1524-e1530. doi: 10.1210/clinem/dgae524.
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.
We evaluated the pathogenicity of 3 novel partial KDM6A duplications identified in 3 individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing.
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 2 individuals to investigate the presence of a KS-specific episignature.
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.
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' in the KDM6A gene.
高胰岛素血症性低血糖症（HI）可能是歌舞伎综合征（KS）的首发症状，KS由KMT2D或KDM6A功能丧失性变异引起。由于这些基因在维持染色质甲基化状态中起关键作用，具有致病变异的个体具有疾病特异性的表观基因组特征——一种表观特征。
我们评估了在3例基因检测时表现为新生儿期HI但无KS典型特征的个体中鉴定出的3种新型KDM6A部分重复的致病性。
通过常规靶向二代测序对HI进行检测，鉴定出3种不同的KDM6A部分重复，最初将其分类为意义未明的变异（VUS），因为其位置以及因此对基因的影响尚不清楚。进行全基因组测序（WGS）以定位重复的断点，并对2例个体进行DNA甲基化分析以研究是否存在KS特异性表观特征。
WGS证实先证者1中的重复是致病性的，因为它导致该基因正常拷贝发生移码，导致提前终止密码子。先证者2和3中鉴定出的重复未改变阅读框，因此WGS后其意义仍不确定。随后的DNA甲基化分析在先证者2中鉴定出KS特异性表观特征，但在先证者3中未鉴定出。
我们的研究结果证实了KDM6A部分基因重复在KS病因中的作用，并强调了进行深入分子遗传分析以正确评估KDM6A基因中VUS临床意义的重要性。
