Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G#x3e;A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.
Mol Syndromol

中文翻译：

---

歌舞伎综合征：鉴定 KMT2D 和 KDM6A 中的两个新变体

歌舞伎综合征 (KS) 是一种罕见的遗传性疾病，其特征在于以下 5 个关键症状：面部畸形、生长迟缓、骨骼异常、智力障碍和皮纹畸形。研究表明，大多数KS病例是由KMT2D基因突变或大量缺失引起，而其他病例则显示KDM6A突变. 我们通过全外显子组测序研究了 2 个无关家族中的 2 名疑似 KS 患者，以确定可能的遗传原因，并通过 Sanger 测序来验证已识别的变异并检查其他家族成员的分离情况。最后，使用计算机预测测试了变体对相应蛋白质结构和功能的潜在影响。两个受影响的家庭成员都表现出典型的 KS 表现，包括智力障碍、发育迟缓和面部特征异常。KMT2D基因中的一个新的杂合移码变体，c.4981del；第（Glu1661Serfs * 61），并在一个新的半合子错义变异体KDM6A基因，c.3301G#x3e；A；p.(Glu1101Lys)，分别在患者 1 和 2 中检测到。在第一个家族中鉴定的移码变体是新的，而在第二个家族中，母亲也是错义变体的杂合子。预计KMT2D 中的移码变体会导致功能受损的截短蛋白质。在第二位患者中受影响的 KDM6A (UTX) 的 Glu1101 残基位于 Jumonji 结构域表面的保守区域，并预测为致病原因。我们的发现为这 2 种变异的可能致病性提供了证据；然而，需要额外的功能研究来确认它们的影响。
摩尔综合征