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.
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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)