Clinical and molecular analysis of Guangxi patients with Kabuki syndrome and KMT2D mutations

Sheng Yi; Xiaofei Zhang; Qi Yang; Jingjing Huang; Xunzhao Zhou; Jiale Qian; Pingshan Pan; Shang Yi; Shujie Zhang; Qiang Zhang; Xianglian Tang; Limei Huang; Qinle Zhang; Zailong Qin; Jingsi Luo

doi:10.1016/j.heliyon.2023.e20223

Clinical and molecular analysis of Guangxi patients with Kabuki syndrome and KMT2D mutations

Heliyon. 2023 Sep 24;9(10):e20223. doi: 10.1016/j.heliyon.2023.e20223. eCollection 2023 Oct.

Authors

Sheng Yi^{1

2}, Xiaofei Zhang^{1

3}, Qi Yang^{1

2}, Jingjing Huang⁴, Xunzhao Zhou^{1

2}, Jiale Qian^{1

3}, Pingshan Pan⁵, Shang Yi^{1

2}, Shujie Zhang^{1

2}, Qiang Zhang^{1

2}, Xianglian Tang^{1

2}, Limei Huang^{1

2}, Qinle Zhang^{1

2}, Zailong Qin^{1

2}, Jingsi Luo^{1

2}

Affiliations

¹ Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
² Guangxi Clinical Research Center for Pediatric Diseases, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Key Laboratory of Precision Medicine for Genetic Diseases, Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Guangxi Key Laboratory of Birth Defects Research and Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
³ Pediatrics Department, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁴ Department of Surgery, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁵ Department of Obstetrics, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.

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.

Keywords: KMT2D; Kabuki syndrome; Motor delay; Non-canonical splicing-site; RNA analysis; Recurrent otitis media.