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Abstract：
Kabuki syndrome (KS) is a multiple congenital anomaly syndrome that is characterized by postnatal growth deficiency, hypotonia, short stature, mild-to-moderate intellectual disability, skeletal abnormalities, persistence of fetal fingertip pads, and distinct facial appearance. It is mainly caused by pathogenic/likely pathogenic variants in the KMT2D or KDM6A genes. Here, we described the clinical features of nine sporadic KS patients with considerable phenotypic heterogeneity. In addition to intellectual disability and short stature, our patients presented with a high prevalence of motor retardation and recurrent otitis media. We recommended that KS should be strongly considered in patients with motor delay, short stature, intellectual disability, language disorder and facial deformities. Nine KMT2D variants, four of which were novel, were identified by whole-exome sequencing. The variants included five nonsense variants, two frameshift variants, one missense variant, and one non-canonical splice site variant. In addition, we reviewed the mutation types of the pathogenic KMT2D variants in the ClinVar database. We also indicated that effective mRNA analysis, using biological materials from patients, is helpful in classifying the pathogenicity of atypical splice site variants. Pedigree segregation analysis may also provide valuable information for pathogenicity classification of novel missense variants. These findings extended the mutation spectrum of KMT2D and provided new insights into the understanding of genotype-phenotype correlations, which are helpful for accurate genetic counseling and treatment optimization.
摘要：
歌舞uki综合征（KS）是一种以出生后生长不足为特征的多发性先天性异常综合征，低张力,身材矮小,轻度至中度智力残疾，骨骼异常,胎儿指尖垫的持久性，和独特的面部外观。它主要是由KMT2D或KDM6A基因中的致病性/可能致病性变体引起的。这里,我们描述了9例具有明显表型异质性的散发性KS患者的临床特征.除了智力残疾和身材矮小，我们的患者表现为运动迟缓和复发性中耳炎的高患病率。我们建议运动延迟患者应强烈考虑KS，身材矮小,智力残疾,语言障碍和面部畸形。九种KMT2D变体，其中四个是小说，通过全外显子组测序鉴定。变体包括五个无义变体，两种移码变体，一个错觉变体，和一个非规范剪接位点变体。此外,我们回顾了ClinVar数据库中致病性KMT2D变异体的突变类型.我们还表明，有效的mRNA分析，使用患者的生物材料，有助于对非典型剪接位点变异的致病性进行分类。谱系分离分析还可以为新型错义变体的致病性分类提供有价值的信息。这些发现扩展了KMT2D的突变谱，并为理解基因型-表型相关性提供了新的见解。这有助于准确的遗传咨询和治疗优化。
