Clinical and molecular genetic characterization of familial MECP2 duplication syndrome in a Chinese family

Xiaoyan Li,Xiaoli Chen,Zhaoshi Yi,Ting Zhang,Qian Chen,Jian Wang,Hua Xie,Xiongying Yu,Erzhen Li,Jianmin Zhong

doi:10.1186/s12881-017-0486-4

Abstract

BackgroundChromosomal duplication at the Xq28 region including the MECP2 gene, share consistent clinical phenotypes and a distinct facial phenotype known as MECP2 duplication syndrome. The typical clinical features include infantile hypotonia, mild dysmorphic features, a broad range of neurodevelopmental disorders, recurrent infections, and progressive spasticity.MethodsThis Chinese MECP2 duplication syndrome family includes six patients (five males and one female), and four asymptomatic female carriers. Two kinds of chips including 4x180K CNV + SNP chip and custom 8x60K CNV chip were used to detect MECP2 duplication, and then fluorescent in situ hybridization (FISH) analysis was performed to identify the exact copy number of MECP2. X-chromosome inactivation (XCI) analysis on AR gene was detected for all female family members, and the microsatellite analysis on MECP2 was used to validate the recombination event on MECP2 region.ResultsThe affected male subjects presented with a broad range of neurodevelopmental symptoms (severe intellectual disability, developmental delay, seizure, language deficit, and autism spectrum disorder) as well as facial dysmorphism and other symptoms which were consistent with that of Western patients previous reported. Seizure is reported in Chinese patients for the first time. In addition, we validated three recombination events for the MECP2-duplication allele during maternal transmission due to X homologous recombination.ConclusionsWe provided the largest known Chinese pedigree with MECP2 duplication syndrome. The detailed clinical description and molecular genetic characterization in all affected family members further delineate the typical phenotype of this genomic disorder in Chinese population.

Highlights

Chromosomal duplication at the Xq28 region including the methyl-CpG-binding protein 2 gene (MECP2) gene, share consistent clinical phenotypes and a distinct facial phenotype known as MECP2 duplication syndrome
We reported familial MECP2 duplication syndrome in a large Chinese family, in which four male patients and four asymptomatic females were confirmed as carrying MECP2 duplication
For 8x60K copy number variants (CNVs) chip, there are 30,000 probes which were designed to cover the entire genome with an average of 30 kb between adjacent probes, allowing for the detections of 300-500 kb CNV on non-X chromosomes

Summary

Introduction

Chromosomal duplication at the Xq28 region including the MECP2 gene, share consistent clinical phenotypes and a distinct facial phenotype known as MECP2 duplication syndrome. XLID can be caused by single nucleotide variants (SNVs) and/ or copy number variants (CNVs) on the X chromosome [2]. The loss-of-function mutation of methyl-CpG-binding protein 2 gene (MECP2) contributes to Rett syndrome [3], while the increased copy number of MECP2 contributes to MECP2 duplication syndrome [4]. With the increased usage of chromosomal microarray or other techniques in clinical diagnostic laboratory, MECP2 duplication can be detected quickly. In China, microarray has been applied for clinical genetic diagnosis only in developed region since 2010 [25,26,27], the exact diagnosis yield of MECP2 duplication in neurodevelopmental

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