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Orphanet J Rare Dis. 2018 Oct 11;13(1):178. doi: 10.1186/s13023-018-0909-0.

Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients.

Li N1,2, Wang Y3, Yang Y4, Wang P5, Huang H6, Xiong S7, Sun L7, Cheng M8, Song C9, Cheng X10, Ding Y3, Chang G3, Chen Y3, Xu Y1, Yu T1,2, Yao RE1,2, Shen Y1,11, Wang X12,13, Wang J14,15,16.

Author information

1
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
2
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
3
Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
4
Department of Endocrinology, Metabolism, and Genetics, Jiangxi Provincial Children's Hospital, Nanchang, 330029, Jiangxi, China.
5
MyGenostics Inc., Beijing, 101318, China.
6
Central laboratory, Jiangxi Provincial Children's Hospital, Nanchang, 330029, Jiangxi, China.
7
Fetal Medicine Unit & Prenatal diagnosis center, Shanghai First Maternity and Infant hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
8
Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
9
Department of Endocrinology and Genetic Metabolic Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders. Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
10
Department of Endocrinology and Metabolism, Chengdu Women's and Children's Central Hospital, Sichuan Province, Chengdu, 610091, China.
11
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
12
Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. wangxiumin1019@126.com.
13
Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China. wangxiumin1019@126.com.
14
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. labwangjian@shsmu.edu.cn.
15
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. labwangjian@shsmu.edu.cn.
16
Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China. labwangjian@shsmu.edu.cn.

Abstract

BACKGROUND:

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts.

METHODS:

Next generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients.

RESULTS:

Genetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes.

CONCLUSION:

Our study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes.

KEYWORDS:

Chinese patients; KMT2A variation; Phenotypic differences; Wiedemann–Steiner syndrome

PMID:
30305169
PMCID:
PMC6180513
DOI:
10.1186/s13023-018-0909-0
[Indexed for MEDLINE]
Free PMC Article

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