Department of Medical Genetics, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada.
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Med Genet A. 2022 May;188(5):1368-1375. doi: 10.1002/ajmg.a.62650. Epub 2022 Jan 18.
Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20-30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome-wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection of another diagnosis in the KS differential, CDK13-related disorder. This approach illustrates the clinical utility of DNAm signatures in the diagnostic workflow for the genome analyst or clinical geneticist-especially for disorders with overlapping clinical phenotypes.
歌舞伎综合征（KS）是一种神经发育障碍，其特征为肌张力低下、智力障碍、骨骼异常和出生后生长受限。特征性面部外观并非 KS 的特异性表现，因为其他几种疾病也具有重叠特征。对于临床诊断为 KS 的 20%-30%的儿童，通过对 KMT2D 和 KDM6A 这两个相关基因的常规基因检测，无法确定其致病变异。在这里，我们描述了两例疑似 KS 的病例，这些病例符合临床诊断标准，并且在人工智能平台 Face2Gene 上具有高度的整体匹配。尽管最初的 KS 检测呈阴性，但全基因组 DNA 甲基化（DNAm）有助于指导基因组测序工作流程，以确定明确的分子诊断。在一个病例中，KDM6A 中的隐匿变异是由 KMT2D 的阳性 DNAm 特征引导基因组测序检测到的；对于另一个病例，与 KS 不同的 DNAm 特征导致在 KS 鉴别诊断中检测到另一种疾病，即 CDK13 相关疾病。这种方法说明了 DNAm 特征在基因组分析员或临床遗传学家的诊断工作流程中的临床应用价值，尤其是对于具有重叠临床表型的疾病。
