A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections
© Xu et al.; licensee BioMed Central Ltd. 2012
Received: 20 June 2012
Accepted: 15 August 2012
Published: 21 August 2012
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.
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.
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.
KeywordsMECP2 Autism ASD CNV Chinese patients
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 . 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. 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 epilepsy. Genome-wide CNV scan using Agilent 1 M comparative genomic hybridization (CGH) microarray showed that both brothers carried a 2.22 Mb MECP2-duplication containing CNV, inherited from their mother. To our knowledge, this is the first report and characterization of MECP2 duplication patients from the Chinese Han population.
Detailed clinical data was gathered from the family. The pedigree is shown in Figure 1A. A girl (G2 P2), born between the two brothers, was born prematurely at 30 weeks, likely because the mother was startled. She died one month after birth. It was noted that she fed very poorly, although her body weight did increase slightly. On the day before she died, she did not feed at all. The cause of death was unknown, as no medical examinations were carried out. It is possible that she also carried the MECP2-containing duplication (no DNA sample available). Although DNA from other members of the mother’s family could not be obtained, the pedigree showed that the mother was the youngest of 5 children, with 2 healthy brothers, and one brother and one sister who died at a young age. The healthy brothers already have grandchildren, and both they and their progeny have no significant health or psychological issues. The older sister died before P01D was born, likely from an accident. The other brother died shortly after birth, for unknown causes. The mother of P01D is over eighty years old, of good health, apart from high blood pressure, and has normal intellectual and social abilities.
Patient 01A (G3 P3 L2) was born at full-term to healthy, nonconsanguineous parents following an uneventful birth, at a birth weight of 3400 g. He showed general developmental delay and was able to walk at the age of 20 months. When examined at the age of 9 years and 5 months, he walked and ran slightly unsteadily and could not jump with both feet off the ground. He was in the normal height range when compared to children of his age, but was slightly slender. In terms of facial features, he had large ears and a depressed nasal bridge. He was slightly hypotonic, but had no history of respiratory infections, has not undergone operations or major medical treatments and has had no seizures or epilepsy. He had no sleep disturbances, but was often constipated. He occasionally got a cold, but was not ill very often. He was hospitalized once at the age of a few months. At the age of 3–4 years, he generated a couple of words, including “mama” and “tea”. Currently, he could only say “mama” and had passive understanding of simple sentences as spoken by his mother, but no other language or echolalia. He could eat a pear by himself, but needed to be fed by his mother for meals, due to difficulty holding a spoon. He occasionally ran around with other children, but could not engage in interactive play. He got very anxious when encountering strangers or when entering a new environment. When happy, he clapped his hands.
Quantification of developmental, cognitive and autism phenotypes of MECP2 duplication-containing patients
Age at examination
9 years 5 months
Bayley Scales of Infant Development-3
Weschler Intelligence Scale
Full Scale IQ
Autism Diagnostic Observation Schedule (ADOS) scores
ADOS communication score
(cutoff score for autism is ≥4)
ADOS social interaction score
(cutoff score for autism is ≥7)
Combined ADOS score (cutoff score for autism is ≥12)
Patient 01B (G1 P1), the older brother of patient 01A, was 18 years old at the time of examination. He was of normal height and weight when compared to his peers. He had mild dysmorphic features including a depressed nasal bridge and midface hypoplasia. He had no history of respiratory infections or other major medical treatments and no history of seizures or epilepsy. He has not been hospitalized, and is otherwise healthy apart from an occasional cold. A previous computed tomography (CT) scan showed no obvious abnormalities. He learnt to walk at 20 months and currently walked and ran slightly unsteadily. He liked to walk on his toes, but could not jump with both feet off the floor. He had no language, but could passively understand simple phrases as spoken by his mother. He was able to eat by himself, and stayed in his room alone at all times other than meal times. He liked to look at cars on the street and was very excited by wheels. When happy, he put his hands to his mouth and laughed loudly. He flapped his hands a lot and did not engage in interaction with others, but laughed often. Although this patient was 18 years at the time of examination, his cognitive, language and motor skills were in the range of 6 to 15 months as measured by Bayley Scales of Infant Development-3  (Table 1). His ADOS score of 17  was well above the cutoff for autistic disorder (Table 1).
Parents of the patients P01A and P01B
Clinical summary of the parents of MECP2 duplication-containing patients
Wechsler Adult Intelligence Scale-Revised
Full Scale IQ
Broad Autism Phenotype Questionnaire (cutoff score in brackets)
Aloof Personality (≤3.25)
Pragmatic language deficits (≤2.75)
Rigid personality (≤3.50)
Total score (≤ 3.15)
Slightly high scores in somatization, depression, anxiety, psychoticism; normal in all other categories
Determination of the precise duplication interval by aCGH
Both Patients 01A and 01B also had a 213.7 kb duplication on Chromosome 2, inherited from their father. This region contained the genes PFN4, LOC375190, C2orf84 and ITSN2. None of these genes have been shown to be associated with autism, and furthermore, since the father is a healthy, normal adult, this CNV is unlikely to be disease-causing by itself. Patient 01A had no other CNVs. Patient 01B had a 48.4 kb duplication on Chromosome 2, containing no known genes, inherited from the mother, and a small deletion (8.2 kb) at 11q13.5, containing GDPD4, inherited from his father. In a previous report , loss of GDPD4 was found as a low frequency de novo CNV in autism patients (3 autism from 1683 analyzed) but not in normal controls. The relationship of GDPD4 to autism is otherwise unknown. In our study, since the GDPD4-containing CNV in Patient 01B is inherited from a healthy parent, it is unlikely to be disease-causing by itself.
Since, based on the existing literature, the other CNVs found in Patients P01A and P01B are unlikely to be the main cause of the patients’ phenotypes, our whole genome CNV results provided further evidence that the main genetic abnormality in patients P01A and P01B is their MECP2-containing duplication, inherited from the mother. The other CNVs could also, in principle, contribute to the patients’ phenotypes in the background of the MECP2-containing duplication. As the MECP2-containing duplication region is relatively large, we also examined whether other genes in the duplicated region could contribute to the phenotype. As shown in Figure 2 and Additional file 2, this region contained 54 genes, including two subunits of the GABA receptor (GABRA3, GABRQ), an isocitrate dehydrogenase (IDH3G), interleukin-1 receptor-associated kinase 1 (IRAK1), the L1 cell adhesion molecule (L1CAM), a PDZ domain protein (PDZD4), Plexin B3 (PLXNB3) and a creatine transporter (SLC6A8) (More details below). Estimation of the association level of this group of genes with autism was carried out using the AutismKB database (http://autismkb.cbi.pku.edu.cn/index.php), an online database that assigned a weighted score to each gene, CNV or linkage region reported to be associated with autism, based on published literature . Using this database, we found that although MECP2 was by far the gene most associated with autism, with a high score of 26, many other genes in the interval also contributed from 3 to 12 points, bringing the score of the entire duplicated region to a very high total of 158 (Additional file 2). The result of this analysis further underscored the importance of this MECP2-containing region to autism.
Size of duplicated region
Compared to other patients with reported duplications in MECP2, the duplicated region of 2.2 Mb identified in family P01 is relatively large. The duplication size in the reported literature is from 0.32 Mb  to 2.56 Mb . The centromeric end of the duplication is located in the 3’ untranslated region of GABRA3 (located on the complementary strand), suggesting potential duplication of a functional copy of the GABRA3 gene. The telomeric end is within FLNA. Since this gene is also located on the complementary strand, and thus the 5’ end and promoter regions are outside of the duplicated region, it is likely that there is no gain-of-function of FLNA. Consistently, the patients did not exhibit the severe, chronic intestinal peudo-obstruction phenotype associated with FLNA duplication . Also worth noting, the telomeric breakpoint is within the 215 kb region distal to MECP2 that has been previously identified as a genomic interval prone to rearrangements resulting in MECP2 duplications .
Although a number of genes in the duplication region have been reported to be associated with autism, the clinical characteristics of our patients fit well with patients carrying just MECP2 duplication [15, 20, 23, 47], the most autism-related gene within the region. IRAK1, the gene neighboring MECP2 and also included in the minimum duplication region [15, 20, 23, 47], is a member of the toll-like receptor-signaling pathway  and has been proposed to contribute to the recurrent infection phenotype in affected boys . Interestingly, although P01A and P01B had Xq28 duplications that clearly included IRAK1, they did not have the recurrent infections reported in some other patients.
Another gene in the duplicated interval with developmental phenotypes is SLC6A8, a creatine transporter whose loss of function resulted in severe intellectual disability and autism [49, 50]. In other MECP2 duplication patients, where the duplicated region also included SLC6A8, creatine levels in spinal fluid and urine were normal, and there were no additional phenotypes . Similarly, our patients did not report any metabolic deficiencies.
The other genes in the duplicated interval reported to be associated with autism are mostly based on CNV studies, rare mutations found during X-chromosome sequencing and/or expression studies (see scores in Additional file 2 and references within the AutismKB database). Since there are no detailed patient descriptions in these large scale studies, it is difficult to establish genotype-phenotype relationships for these genes. It is possible that some of these genes may affect the patient’s clinical characteristics in the background of MECP2 duplication. Of particular interest in this group are GABA receptor subunits GABRA3 and GABRQ, components of GABAergic neurotransmission. GABA is the main inhibitory neurotransmitter in the brain, and alterations of GABAergic signaling are thought to be associated with ASD . Also of interest are synaptic components and cell adhesion molecules, which have recently been associated with autism . Duplicated genes in this category include: L1CAM, encoding the L1 cell adhesion molecule; PDZD4, the PDZ domain containing and potential post-synaptic scaffold protein, and PLXNB3, the axon guidance molecule Plexin B3, which acts as a receptor for the Semaphorin 5A signal.
Clinical features of boys with duplicated MECP2
Our results are consistent with previous reports showing lack of correlation between duplication size and clinical phenotypes, as the patients we identified are no more severe than those with much smaller duplications [14, 15, 23, 26, 27, 47].
In this study, we identified a Chinese Han family with two brothers carrying a MECP2-containing duplication inherited from their mother. The duplicated region, as defined by microarray analysis, was 2.22 Mb in size. To our knowledge, this is the first report of Chinese Han autistic patients with MECP2 duplication. These individuals shared many characteristics with previously reported MECP2 duplication patients [9–27], including autism, intellectual disability, hypotonia and mild dysmorphic features, but not recurrent respiratory infections or epilepsy. Identification and characterization of more patients are needed for studies regarding potential differences in phenotype between ethnic groups, as well as for the correlation between duplication size and clinical phenotype. Importantly, our results demonstrate that MECP2 duplication is present in autism patients of Chinese Han ethnicity, likely at an occurrence rate suitable for genetic testing.
This study was approved by the Ethics Committee of the Children’s Hospital of Fudan University (Approval number: Children’s Hospital of Fudan University Ethics Protocol 2011–040; Title: Research on the behavioral phenotype and genetic basis of autism spectrum disorder). Written informed consent for the collection of peripheral blood samples and subsequent analyses was obtained from all participating families, with the parents giving consent for themselves and on behalf of their minor children. A copy of the written consent is available for review by the Editor-in-Chief of this Journal.
XX, ZQ and XY conceived the study and participated in its design and coordination; XX, QX, YZ, BW, YD, and PL identified the patients and carried out the clinical characterizations; XZ, TC, JZ, and MZ carried out the molecular genetics studies; XY wrote the manuscript; all authors read and approved the final manuscript.
We thank all the children and their families for participating in this study, and thank Ms. Congxiao Yu (Wenmiao Kindergarten, Shanghai) for support in organizing the control subjects for the CGH analysis of this study. We thank Dr. Feng Zhang from Fudan University for advice on CNV analysis. This study was supported by 973 grant 2011CBA00400 from the Ministry of Science and Technology (to XX, ZQ, and XY), grants 31021063 and 31125015 from the National Science Foundation of China (to XY), the Hundred Talent Program from the Chinese Academy of Sciences (to ZQ), and grants GWDTR201220 and 12GWZX0301 from the Shanghai Municipal Health Bureau (to XX).
- Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008, 9 (5): 341-355. 10.1038/nrg2346.View ArticlePubMedPubMed CentralGoogle Scholar
- Folstein SE, Rosen-Sheidley B: Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001, 2 (12): 943-955. 10.1038/35103559.View ArticlePubMedGoogle Scholar
- Freitag CM: The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry. 2007, 12 (1): 2-22. 10.1038/sj.mp.4001896.View ArticlePubMedGoogle Scholar
- Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, Fauchereau F, Coleman M, Leboyer M, Gillberg C, Bourgeron T: Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet. 2010, 26 (8): 363-372. 10.1016/j.tig.2010.05.007.View ArticlePubMedGoogle Scholar
- Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, et al: A copy number variation morbidity map of developmental delay. Nat Genet. 2011, 43 (9): 838-846. 10.1038/ng.909.View ArticlePubMedPubMed CentralGoogle Scholar
- Rett A: Cerebral atrophy associated with hyperammonaemia. Handbook of Clinical Neurology. Edited by: Vinken PJ, Bruyn GW. 1977, Elsevier, Amsterdam, 305-329. 29Google Scholar
- Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999, 23 (2): 185-188. 10.1038/13810.View ArticlePubMedGoogle Scholar
- Moretti P, Zoghbi HY: MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. 2006, 16 (3): 276-281. 10.1016/j.gde.2006.04.009.View ArticlePubMedGoogle Scholar
- Nomura Y: Early behavior characteristics and sleep disturbance in Rett syndrome. Brain Dev. 2005, 27 (Suppl 1): S35-S42.View ArticlePubMedGoogle Scholar
- Belligni EF, Palmer RW, Hennekam RC: MECP2 duplication in a patient with congenital central hypoventilation. Am J Med Genet A. 2010, 152A (6): 1591-1593.PubMedGoogle Scholar
- Breman AM, Ramocki MB, Kang SH, Williams M, Freedenberg D, Patel A, Bader PI, Cheung SW: MECP2 duplications in six patients with complex sex chromosome rearrangements. Eur J Hum Genet. 2010, 19 (4): 409-415.View ArticlePubMedPubMed CentralGoogle Scholar
- Budisteanu M, Papuc SM, Tutulan-Cunita A, Budisteanu B, Arghir A: Novel clinical finding in MECP2 duplication syndrome. Eur Child Adolesc Psychiatry. 2011, 20 (7): 373-375. 10.1007/s00787-011-0184-2.View ArticlePubMedGoogle Scholar
- Campos M, Churchman SM, Santos-Reboucas CB, Ponchel F, Pimentel MM: High frequency of nonrecurrent MECP2 duplications among Brazilian males with mental retardation. J Mol Neurosci. 2010, 41 (1): 105-109. 10.1007/s12031-009-9296-2.View ArticlePubMedGoogle Scholar
- Clayton-Smith J, Walters S, Hobson E, Burkitt-Wright E, Smith R, Toutain A, Amiel J, Lyonnet S, Mansour S, Fitzpatrick D, et al: Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur J Hum Genet. 2009, 17 (4): 434-443. 10.1038/ejhg.2008.192.View ArticlePubMedGoogle Scholar
- del Gaudio D, Fang P, Scaglia F, Ward PA, Craigen WJ, Glaze DG, Neul JL, Patel A, Lee JA, Irons M, et al: Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med. 2006, 8 (12): 784-792. 10.1097/01.gim.0000250502.28516.3c.View ArticlePubMedGoogle Scholar
- Echenne B, Roubertie A, Lugtenberg D, Kleefstra T, Hamel BC, Van Bokhoven H, Lacombe D, Philippe C, Jonveaux P, de Brouwer AP: Neurologic aspects of MECP2 gene duplication in male patients. Pediatr Neurol. 2009, 41 (3): 187-191. 10.1016/j.pediatrneurol.2009.03.012.View ArticlePubMedGoogle Scholar
- Friez MJ, Jones JR, Clarkson K, Lubs H, Abuelo D, Bier JA, Pai S, Simensen R, Williams C, Giampietro PF, et al: Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics. 2006, 118 (6): e1687-e1695. 10.1542/peds.2006-0395.View ArticlePubMedGoogle Scholar
- Kirk EP, Malaty-Brevaud V, Martini N, Lacoste C, Levy N, Maclean K, Davies L, Philip N, Badens C: The clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA. Clin Genet. 2009, 75 (3): 301-303.View ArticlePubMedGoogle Scholar
- Lugtenberg D, de Brouwer AP, Kleefstra T, Oudakker AR, Frints SG, Schrander-Stumpel CT, Fryns JP, Jensen LR, Chelly J, Moraine C, et al: Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH. J Med Genet. 2006, 43 (4): 362-370.View ArticlePubMedGoogle Scholar
- Lugtenberg D, Kleefstra T, Oudakker AR, Nillesen WM, Yntema HG, Tzschach A, Raynaud M, Rating D, Journel H, Chelly J, et al: Structural variation in Xq28: MECP2 duplications in 1 % of patients with unexplained XLMR and in 2 % of male patients with severe encephalopathy. Eur J Hum Genet. 2009, 17 (4): 444-453. 10.1038/ejhg.2008.208.View ArticlePubMedGoogle Scholar
- Meins M, Lehmann J, Gerresheim F, Herchenbach J, Hagedorn M, Hameister K, Epplen JT: Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J Med Genet. 2005, 42 (2): e12-10.1136/jmg.2004.023804.View ArticlePubMedPubMed CentralGoogle Scholar
- Prescott TE, Rodningen OK, Bjornstad A, Stray-Pedersen A: Two brothers with a microduplication including the MECP2 gene: rapid head growth in infancy and resolution of susceptibility to infection. Clin Dysmorphol. 2009, 18 (2): 78-82. 10.1097/MCD.0b013e32831e19cd.View ArticlePubMedGoogle Scholar
- Ramocki MB, Peters SU, Tavyev YJ, Zhang F, Carvalho CM, Schaaf CP, Richman R, Fang P, Glaze DG, Lupski JR, et al: Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol. 2009, 66 (6): 771-782. 10.1002/ana.21715.View ArticlePubMedPubMed CentralGoogle Scholar
- Reardon W, Donoghue V, Murphy AM, King MD, Mayne PD, Horn N, Birk Moller L: Progressive cerebellar degenerative changes in the severe mental retardation syndrome caused by duplication of MECP2 and adjacent loci on Xq28. Eur J Pediatr. 2010, 169 (8): 941-949. 10.1007/s00431-010-1144-4.View ArticlePubMedGoogle Scholar
- Sanlaville D, Prieur M, de Blois MC, Genevieve D, Lapierre JM, Ozilou C, Picq M, Gosset P, Morichon-Delvallez N, Munnich A, et al: Functional disomy of the Xq28 chromosome region. Eur J Hum Genet. 2005, 13 (5): 579-585. 10.1038/sj.ejhg.5201384.View ArticlePubMedGoogle Scholar
- Smyk M, Obersztyn E, Nowakowska B, Nawara M, Cheung SW, Mazurczak T, Stankiewicz P, Bocian E: Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections. Am J Med Genet B Neuropsychiatr Genet. 2008, 147B (6): 799-806. 10.1002/ajmg.b.30683.View ArticlePubMedGoogle Scholar
- Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, et al: Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet. 2005, 77 (3): 442-453. 10.1086/444549.View ArticlePubMedPubMed CentralGoogle Scholar
- Velinov M, Novelli A, Gu H, Fenko M, Dolzhanskaya N, Bernardini L, Capalbo A, Dallapiccola B, Jenkins EC, Brown WT: De-novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation. Clin Dysmorphol. 2009, 18 (1): 9-12. 10.1097/MCD.0b013e3283157cad.View ArticlePubMedGoogle Scholar
- Ramocki MB, Tavyev YJ, Peters SU: The MECP2 duplication syndrome. Am J Med Genet A. 2010, 152A (5): 1079-1088. 10.1002/ajmg.a.33184.View ArticlePubMedPubMed CentralGoogle Scholar
- Chen RZ, Akbarian S, Tudor M, Jaenisch R: Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001, 27 (3): 327-331. 10.1038/85906.View ArticlePubMedGoogle Scholar
- Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David Sweatt J, Zoghbi HY: Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet. 2004, 13 (21): 2679-2689. 10.1093/hmg/ddh282.View ArticlePubMedGoogle Scholar
- Guy J, Hendrich B, Holmes M, Martin JE, Bird A: A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001, 27 (3): 322-326. 10.1038/85899.View ArticlePubMedGoogle Scholar
- Luikenhuis S, Giacometti E, Beard CF, Jaenisch R: Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA. 2004, 101 (16): 6033-6038. 10.1073/pnas.0401626101.View ArticlePubMedPubMed CentralGoogle Scholar
- Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H: Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron. 2002, 35 (2): 243-254. 10.1016/S0896-6273(02)00768-7.View ArticlePubMedGoogle Scholar
- Xi CY, Lu Y, Tan YH, Hua TY, Zhao YJ, Liu XM, Gao H: Analysis of MECP2 gene copy number in boys with autism. J Child Neurol. 2011, 26 (5): 570-573. 10.1177/0883073810387138.View ArticlePubMedGoogle Scholar
- Du R, Lu C, Jiang Z, Li S, Ma R, An H, Xu M, An Y, Xia Y, Jin L, et al: Efficient typing of copy number variations in a segmental duplication-mediated rearrangement hotspot using multiplex competitive amplification. J Hum Genet. 2012, 10.1038/ jhg.2012.66.Google Scholar
- Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M: Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995, 25 (1): 63-77. 10.1017/S0033291700028099.View ArticlePubMedGoogle Scholar
- Association AP: Diagnostic and Statistical Manual of Mental Disorders. 1994, American Psychiatric Association, Washington, DCGoogle Scholar
- Lord C, Rutter M, DiLavore PC, Risi S: Austism Diagnostic Observation Schedule. 1999, Western Psychological Corporation, Los Angeles, CAGoogle Scholar
- Derogatis LR, Lipman RS, Covi L: SCL-90: an outpatient psychiatric rating scale–preliminary report. Psychopharmacol Bull. 1973, 9 (1): 13-28.PubMedGoogle Scholar
- Wang Z-Y: Symptom Checklist 90 (SCL90) in Chinese. Shanghai Archives of Psychiatry. 1984, 02: 68-70.Google Scholar
- Gong YS: Wechsler Adult Intelligence Scale - Revised, in Chinese. 1992, HNDTCBS, ChangshaGoogle Scholar
- Wechsler D: Wechsler Adult Intelligence Scale - Revised. 1981, Pscyhological Corporation, San Antonio, TXGoogle Scholar
- Hurley RS, Losh M, Parlier M, Reznick JS, Piven J: The broad autism phenotype questionnaire. J Autism Dev Disord. 2007, 37 (9): 1679-1690. 10.1007/s10803-006-0299-3.View ArticlePubMedGoogle Scholar
- Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, Alvarez Retuerto AI, Imielinski M, Hadley D, Bradfield JP, et al: Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009, 5 (6): e1000536-10.1371/journal.pgen.1000536.View ArticlePubMedPubMed CentralGoogle Scholar
- Xu LM, Li JR, Huang Y, Zhao M, Tang X, Wei L: AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic Acids Res. 2012, 40 (Database issue): D1016-1022.View ArticlePubMedGoogle Scholar
- Carvalho CM, Zhang F, Liu P, Patel A, Sahoo T, Bacino CA, Shaw C, Peacock S, Pursley A, Tavyev YJ, et al: Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet. 2009, 18 (12): 2188-2203. 10.1093/hmg/ddp151.View ArticlePubMedPubMed CentralGoogle Scholar
- Gottipati S, Rao NL, Fung-Leung WP: IRAK1: a critical signaling mediator of innate immunity. Cell Signal. 2008, 20 (2): 269-276. 10.1016/j.cellsig.2007.08.009.View ArticlePubMedGoogle Scholar
- Newmeyer A, de Grauw T, Clark J, Chuck G, Salomons G: Screening of male patients with autism spectrum disorder for creatine transporter deficiency. Neuropediatrics. 2007, 38 (6): 310-312. 10.1055/s-2008-1065353.View ArticlePubMedGoogle Scholar
- Poo-Arguelles P, Arias A, Vilaseca MA, Ribes A, Artuch R, Sans-Fito A, Moreno A, Jakobs C, Salomons G: X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism. J Inherit Metab Dis. 2006, 29 (1): 220-223. 10.1007/s10545-006-0212-4.View ArticlePubMedGoogle Scholar
- Pizzarelli R, Cherubini E: Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 2011, 2011: 297153-PubMedPubMed CentralGoogle Scholar
- Zoghbi HY, Bear MF: Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol. 2012, 4: 3-View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/75/prepub