Kabuki syndrome: novel pathogenic variants, new phenotypes and review of literature

Huakun Shangguan,Chunxiu Gong,Chunxiu Gong,Bingyan Cao,Jian Wang,Jian Wang,Chang Su,Chang Su,Ruimin Chen,Bingyan Cao,Qian Ouyang

doi:10.1186/s13023-019-1219-x

Abstract

ObjectiveThis study describes 5 novel variants of 7 KMT2D/KDM6A gene and summarizes the clinical manifestations and the mutational spectrum of 47 Chinese Kabuki syndrome (KS) patients.MethodsBlood samples were collected for whole-exome sequencing (WES) for 7 patients and their parents if available. Phenotypic and genotypic spectra of 40 previously published unrelated Chinese KS patients were summarized.ResultGenetic sequencing identified six KMT2D variants (c.3926delC, c.5845delC, c.6595delT, c.12630delG, c.16294C > T, and c.16442delG) and one KDM6A variant (c.2668-2671del). Of them, 4 variants (c.3926delC, c.5845delC, c.12630delG, and c.16442delG) in KMT2D gene and the variant (c.2668-2671del) in KDM6A gene were novel. Combining with previously published Chinese KS cases, the patients presented with five cardinal manifestations including facial dysmorphism, intellectual disability, growth retardation, fingertip pads and skeletal abnormalities. In addition, 29.5% (5/17) patients had brain abnormalities, such as hydrocephalus, cerebellar vermis dysplasia, thin pituitary and white matter myelination delay, corpus callosum hypoplasia and Dandy-Walker malformation.ConclusionIn this report, five novel variants in KMT2D/KDM6A genes are described. A subset of Chinese KS patients presented with brain abnormalities that were not previously reported. Our study expands the mutational and phenotypic spectra of KS.

Highlights

Kabuki syndrome (KS, OMIM#147920) is a rare syndrome with multiple congenital anomalies
The causative gene of KS was identified in 2010 when Bögershausen et al [3] reported de novo heterozygous variants in lysine-specific methyltransferase 2D (KMT2D) gene, which is located on chromosome 12q13
We evaluated the phenotype spectra of Shangguan et al Orphanet Journal of Rare Diseases (2019) 14:255 all Chinese KS patients and paid particular attention to the brain abnormalities among a total of 47 unrelated Chinese KS patients

Summary

Introduction

Kabuki syndrome (KS, OMIM#147920) is a rare syndrome with multiple congenital anomalies It was first reported by Japanese researchers Kuroki and Niikawa [1, 2]. In 2012, variants in the KDM6A gene, which is located on Consistent features of KS included distinctive facial dysmorphism (long palpebral fissures, depressed nasal tip and large ears), short stature, intellectual disability, skeletal abnormalities and dermatoglypic abnormalities. Other recurrent features such as congenital cardiac anomalies, ureter malformation and hip joint dislocation had been reported in non-Chinese KS patients [5]. There is little information about brain abnormalities in KS patients

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