A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

BMC Medical Genetics, Aug 2012

Background Autistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. Case presentation Here, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 – 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy. Conclusions To our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.

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A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

Xiu Xu 1 Qiong Xu 1 Ying Zhang 1 Xiaodi Zhang 0 Tianlin Cheng 0 Bingbing Wu 1 Yanhua Ding 1 Ping Lu 1 Jingjing Zheng 0 Min Zhang 0 Zilong Qiu 0 Xiang Yu 0 0 Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China 1 Department of Child Healthcare, Children's Hospital of Fudan University , Shanghai , China Background: Autistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. Case presentation: Here, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2containing duplication (151,369,305 - 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy. Conclusions: To our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients. - Background Autism spectrum disorders (ASDs) are neurodevelopmental disorders with complex etiology and strong genetic basis, characterized by impaired communication, reduced social interaction, and stereotyped and/or repetitive behavior [1-4]. Over the past decade, an emergent feature regarding the genetics of ASD is the importance of gene dosage, where both loss and gain of function of a gene can result in autistic phenotypes [4,5]. A prominent example is the Methyl-CpG-binding Protein 2 gene (MECP2; MIM: 300005), located at Xq28. Loss of function of one copy of MECP2 leads to Rett syndrome (RTT; MIM 312750), a progressive neurodevelopmental disorder characterized by loss of motor skills and communication abilities, as well as stereotypic hand movements and other autistic features, occurring in 1:10,000 girls [6-9]. More recently, duplication of the MECP2 gene has been found in boys with developmental delay, intellectual disability and/or autism in a series of studies [10-28]. Core features of the syndrome included infantile hypotonia, mild dysmorphic features, developmental delay, intellectual disability, abnormal movement and absent to minimal speech. Although not all studies examined autistic characteristics, when the examinations were carried out, autistic phenotypes were prominent among patients with MECP2 duplication [15,21,23,29]. In fact, of 8 boys evaluated using the Autism Diagnostic Observation Schedule (ADOS) in one study, 7 (88%) exceeded the cutoff score for autism, while the remaining one exceeded the score for ASD [23]. Thus altering the gene dosage of MECP2 by both deletion and duplication can generate autistic phenotypes. Corroborating these clinical findings, similarities in phenotypes, including autistic features, were observed both in mouse models of MECP2 deletions and duplications [30-34]. Whether MECP2 duplication is a cause of intellectual disability and/or autism in the Chinese Han population is unknown. A previous study screening 82 Chinese Han boys diagnosed with autism using real-time quantitative polymerase chain reaction (qPCR) failed to identify deletions or duplications in MECP2 [35]. Since the sample size was small, the question of whether MECP2 duplication is present in Chinese patients diagnosed with autism required further study. Here, we report two brothers diagnosed with autistic disorder carrying duplication in MECP2, inherited from their mother. Detailed examination, medical history inquiry and characterization by ADOS showed that these boys shared many characteristics with previously reported patients carrying duplication encompassing the MECP2 gene [10-28], including autism, intellectual disability, hypotonia and mild dysmorphic features, but not recurrent respiratory infections or e (...truncated)


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Xiu Xu, Qiong Xu, Ying Zhang, Xiaodi Zhang, Tianlin Cheng, Bingbing Wu, Yanhua Ding, Ping Lu, Jingjing Zheng, Min Zhang, Zilong Qiu, Xiang Yu. A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections, BMC Medical Genetics, 2012, pp. 75, 13, DOI: 10.1186/1471-2350-13-75