Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).
EllisonKAFillCPTerwilligerJ. Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis. Am J Hum Genet. 1992;50(2):278–287.
2.
SchanenNCDahleEJCapozzoliF. A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map. Am J Hum Genet. 1997;61(3):634–641.
3.
SchanenCFranckeU. A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. Am J Hum Genet. 1998;63(1):267–269.
4.
SirianniNNaiduSPereiraJ. Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet. 1998;63(5):1552–1558.
5.
MnatzakanianGNLohiHMunteanuI. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004;36(4):339–341.
6.
NanXMeehanRRBirdA. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 1993;21(21):4886–4892.
7.
WakefieldRISmithBONanX. The solution structure of the domain from MeCP2 that binds to methylated DNA. J Mol Biol. 1999;291(5):1055–1065.
8.
NanXCampoyFJBirdA. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88(4):471–481.
9.
JonesPLVeenstraGJWadePA. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19(2):187–191.
10.
LewisJDMeehanRRHenzelWJ. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell. 1992;69(6):905–914.
11.
NanXTatePLiEBirdA. DNA methylation specifies chromosomal localization of MeCP2. Mol Cell Biol. 1996;16(1):414–421.
12.
ChandlerSPGuschinDLandsbergerNWolffeAP. The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA. Biochemistry. 1999;38(22):7008–7018.
13.
JungBPJugloffDGZhangG. The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J Neurobiol. 2003;55(1):86–96.
14.
ChenRZAkbarianSTudorMJaenischR. 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.
15.
ChenWGChangQLinY. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003;302(5646):885–889.
16.
MartinowichKHattoriDWuH. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003;302(5646):890–893.
17.
ZhouZHongEJCohenS. Brain-specific phosphorylation of MeCP2 regulates activity-dependent bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52(2):255–269.
18.
StanchevaICollinsALVan den VeyverIB. A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol Cell. 2003;12(2):425–435.
19.
HorikeSCaiSMiyanoM. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet. 2005;37(1):31–40.
20.
PeddadaSYasuiDHLaSalleJM. Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. Hum Mol Genet. 2006;15(12):2003–2014.
21.
NuberUAKriaucionisSRoloffTC. Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet. 2005;14(15):2247–2256.
22.
ItohMIdeSTakashimaS. Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains. J Neuropathol Exp Neurol. 2007;66(2):117–123.
23.
KriaucionisSPatersonACurtisJ. Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol. 2006;26(13):5033–5042.
24.
DengVMatagneVBanineF. FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet. 2007;16(6):640–650.
25.
McGillBEBundleSFYaylaogluMB. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2006;103(48):18267–18272.
26.
SamacoRCHogartALaSalleJM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005;14(4):483–492.
27.
ChahrourMZoghbiHY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56(3):422–437.
28.
HagbergB. Rett’s syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatr Scand. 1985;74(3):405–408.
29.
ImessaoudeneBBonnefontJP, Royer G, et al. MECP2mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet. 2001;38(3):171–174.
30.
GeerdinkNRotteveelJJLammensM. MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings. Neuropediatrics. 2002;33(1):33–36.
31.
ArmstrongJPinedaMAibarE. Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation. Ann Neurol. 2001;50(5):692.
32.
BuddenSSDorseyHCSteinerRD. Clinical profile of a male with Rett syndrome. Brain Dev. 2005;27(suppl 1):S69–S71.
33.
KankirawatanaPLeonardHEllawayC. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006;67(1):164–166.
34.
LeonardHSilbersteinJFalkR. Occurrence of Rett syndrome in boys. J Child Neurol. 2001;16(5):333–338.
35.
LeuzziVDi SabatoMLZollinoM. Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation. Neurology. 2004;63(10):1968–1970.
36.
LundvallMSamuelssonLKyllermanM. Male Rett phenotypes in T158M and R294X MeCP2-mutations. Neuropediatrics. 2006;37(5):296–301.
37.
MasuyamaTMatsuoMJingJJ. Classic Rett syndrome in a boy with R133C mutation of MECP2. Brain Dev. 2005;27(6):439–442.
38.
RettA. On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien Med Wochenschr. 1966;116(37):723–726.
39.
HagbergBAicardiJDiasKRamosO. Aprogressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol. 1983;14(4):471–479.
40.
TrevathanENaiduS. The clinical recognition and differential diagnosis of Rett syndrome. J Child Neurol. 1988;3(suppl):S6–S16.
41.
HagbergBHanefeldFPercyASkjeldalO. An update on clinically applicable diagnostic criteria in Rett syndrome: comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol. 2002;6(5):293–297.
42.
AmirREVan den VeyverIBWanM. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–188.
43.
BienvenuTCarrieAde RouxN. MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet. 2000;9(9):1377–1384.
44.
SmeetsETerhalPCasaerP. Rett syndrome in females with CTS hot spot deletions: a disorder profile. Am J Med Genet A. 2005;132(2):117–120.
45.
BourdonVPhilippeCLabruneO. A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients. Hum Genet. 2001;108(1):43–50.
46.
HampsonKWoodsCGLatifFWebbT. Mutations in the MECP2 gene in a cohort of girls with Rett syndrome. J Med Genet. 2000;37(8):610–612.
47.
KammounFde RouxNBoespflug-TanguyO. Screening of MECP2 coding sequence in patients with phenotypes of decreasing likelihood for Rett syndrome: a cohort of 171 cases. J Med Genet. 2004;41(6):e85.
48.
LacconeFJunemannIWhatleyS. Large deletions of the MECP2 gene detected by gene dosage analysis in patients with Rett syndrome. Hum Mutat. 2004;23(3):234–244.
49.
LacconeFHuppkePHanefeldFMeinsM. Mutation spectrum in patients with Rett syndrome in the German population: evidence of hot spot regions. Hum Mutat. 2001;17(3):183–190.
50.
Miltenberger-MiltenyiGLacconeF. Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. Hum Mutat. 2003; 22(2):107–115.
51.
XiangFBuervenichSNicolaoP. Mutation screening in Rett syndrome patients. J Med Genet. 2000;37(4):250–255.
52.
ObataKMatsuishiTYamashitaY. Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome. J Med Genet. 2000;37(8):608–610.
53.
PercyAKLaneJB. Rett syndrome: clinical and molecular update. Curr Opin Pediatr. 2004;16(6):670–677.
54.
ZappellaMMeloniILongoI. Preserved speech variants of the Rett syndrome: molecular and clinical analysis. Am J Med Genet. 2001;104(1):14–22.
55.
KlauckSMLindsaySBeyerKS. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am J Hum Genet. 2002;70(4):1034–1037.
56.
YaronYBen ZeevBShomratR. MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome. Hum Mutat. 2002;20(4):323–324.
57.
SchollenESmeetsEDeflemE. Gross rearrangements in the MECP2 gene in three patients with Rett syndrome: implications for routine diagnosis of Rett syndrome. Hum Mutat. 2003;22(2):116–120.
58.
ErlandsonASamuelssonLHagbergB. Multiplex ligation-dependent probe amplification (MLPA) detects large deletions in the MECP2 gene of Swedish Rett syndrome patients. Genet Test. 2003;7(4):329–332.
59.
ArianiFMariFPescucciC. Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: report of one case of MECP2 deletion and one case of MECP2 duplication. Hum Mutat. 2004;24(2):172–177.
60.
RavnKNielsenJBSkjeldalOH. Large genomic rearrangements in MECP2. Hum Mutat. 2005;25(3):324.
61.
HuppkePOhlenbuschABrendelC. Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2. Am J Med Genet A. 2005;137(2):136–138.
62.
ShiJShibayamaALiuQ. Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by robust dosage PCR (RD-PCR). Hum Mutat. 2005;25(5):505.
63.
ArcherHLWhatleySDEvansJC. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet. 2006;43(5):451–456.
64.
ScalaELongoIOttimoF. MECP2 deletions and genotype-phenotype correlation in Rett syndrome. Am J Med Genet A. 2007;143(23):2775–2784.
65.
HardwickSAReuterKWilliamsonSL. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. Eur J Hum Genet. 2007;15(12):1218–1229.
66.
LachlanKLCollinsonMNSandfordRO. Functional disomy resulting from duplications of distal Xq in four unrelated patients. Hum Genet. 2004;115(5):399–408.
67.
ChenCPLinCCLiYC. Primary ovarian failure in a mentally retarded woman with a de novo unbalanced X;autosome translocation. Fertil Steril. 2006;86(5):1514.e1–1514.e2.
68.
MerhiZORobertsJLAwonugaAO. A case of 46,X,der(X) t(X;X)(q22.1;p11) Xq22.1→Xqter in a 12-year-old girl with premature ovarian failure. Gynecol Obstet Invest. 2007;63(3):137–139.
69.
PortnoiMFAbouraATachdjianG. Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients. Hum Reprod. 2006;21(9):2329–2334.
70.
PrueittRLChenHBarnesRIZinnAR. Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes. Cytogenet Genome Res. 2002;97(1-2):32–38.
71.
RossettiFRizzolioFPramparoT. A susceptibility gene for premature ovarian failure (POF) maps to proximal Xq28. Eur J Hum Genet. 2004;12(10):829–834.
72.
EggermannTMeschedeDSchulerH. Premature ovarian failure associated with a small terminal Xq deletion: narrowing the POF1 region down to Xq27.2/Xq27.3-qter. Clin Genet. 2005;67(5):434–437.
73.
ArmstrongDD. Rett syndrome neuropathology review 2000. Brain Dev. 2001;23(suppl 1):S72–S76.
74.
SchwartzmanJSBernardinoANishimuraA. Rett syndrome in a boy with a 47, XXY karyotype confirmed by a rare mutation in the MECP2 gene. Neuropediatrics. 2001;32(3):162–164.
75.
KleefstraTYntemaHGNillesenWM. MECP2analysis in mentally retarded patients: implications for routine DNA diagnostics. Eur J Hum Genet. 2004;12(1):24–28.
76.
WanMLeeSSZhangX. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999;65(6):1520–1529.
77.
VillardLKpebeACardosoCChellyPJ. Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology. 2000;55(8):1188–1193.
78.
ZeevBBYaronYSchanenNC. Rett syndrome: clinical manifestations in males with MECP2 mutations. J Child Neurol. 2002;17(1):20–24.
79.
HoffbuhrKDevaneyJMLaFleurB. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001;56(11):1486–1495.
80.
RavnKNielsenJBUldallP. No correlation between phenotype and genotype in boys with a truncating MECP2 mutation. J Med Genet. 2003;40(1):e5.
81.
Clayton-SmithJWatsonPRamsdenSBlackGC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet. 2000;356(9232):830–832.
82.
TopcuMAkyerliCSayiA. Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur J Hum Genet. 2002;10(1):77–81.
83.
DayerAGBottaniABouchardyI. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. 2007;29(1):47–50.
84.
MeloniIBruttiniMLongoI. A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet. 2000;67(4):982–985.
85.
CouvertPBienvenuTAquavivaC. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001;10(9):941–946.
86.
OrricoALamCGalliL. MECP2 mutation in male patients with non-specific X-linked mental retardation. FEBS Lett. 2000;481(3):285–288.
87.
JedeleKB. The overlapping spectrum of Rett and Angelman syndromes: a clinical review. Semin Pediatr Neurol. 2007;14(3):108–117.
88.
WatsonPBlackGRamsdenS. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001;38(4):224–228.
89.
JiangYLev-LehmanEBresslerJ. Genetics of Angelman syndrome. Am J Hum Genet. 1999;65(1):1–6.
90.
YntemaHGKleefstraTOudakkerAR. Low frequency of MECP2 mutations in mentally retarded males. Eur J Hum Genet. 2002;10(8):487–490.
91.
YntemaHGOudakkerARKleefstraT. In-frame deletion in MECP2 causes mild nonspecific mental retardation. Am J Med Genet. 2002;107(1):81–83.
92.
BourdonVPhilippeCMartinD. MECP2 mutations or polymorphisms in mentally retarded boys: diagnostic implications. Mol Diagn. 2003;7(1):3–7.
93.
HarveyCGMenonSDStachowiakB. Sequence variants within exon 1 of MECP2 occur in females with mental retardation. Am J Med Genet B Neuropsychiatr Genet. 2007;144(3):355–360.
LamCWYeungWLKoCH. Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet. 2000;37(12):E41.
96.
CarneyRMWolpertCMRavanSA. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol. 2003;28(3):205–211.
97.
ZappellaMMeloniILongoI. Study of MECP2 gene in Rett syndrome variants and autistic girls. Am J Med Genet B Neuropsychiatr Genet. 2003;119(1):102–107.
98.
ShibayamaACookEHJrFengJMECP2 structural and 3′-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism. Am J Med Genet B Neuropsychiatr Genet. 2004;128(1):50–53.
99.
CoutinhoAMOliveiraGKatzC. MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2007;144(4):475–483.
100.
Abdul-RahmanOAHudginsL. The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders. Genet Med. 2006;8(1):50–54.
101.
HughesINewtonR. Genetic aspects of cerebral palsy. Dev Med Child Neurol. 1992;34(1):80–86.
BundeySGriffithsMI. Recurrence risks in families of children with symmetrical spasticity. Dev Med Child Neurol. 1977;19(2):179–191.
104.
PettersonBStanleyFHendersonD. Cerebral palsy in multiple births in Western Australia: genetic aspects. Am J Med Genet. 1990;37(3):346–351.
105.
LaplazaFJRootLTassanawipasACerveraP. Cerebral palsy in twins. Dev Med Child Neurol. 1992;34(12):1053–1063.
106.
FletcherNAFoleyJ. Parental age, genetic mutation, and cerebral palsy. J Med Genet. 1993;30(1):44–46.
107.
MitchellSBundeyS. Symmetry of neurological signs in Pakistani patients with probable inherited spastic cerebral palsy. Clin Genet. 1997;51(1):7–14.
108.
SchaeferGB. Genetics considerations in cerebral palsy. Semin Pediatr Neurol. 2008;15(1):21–26.
109.
CollinsALLevensonJMVilaythongAP. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet. 2004;13(21):2679–2689.
110.
del GaudioDFangPScagliaF. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med. 2006;8(12):784–792.
111.
FriezMJJonesJRClarksonK. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics. 2006;118(6):e1687–e1695.
112.
Van EschHBautersMIgnatiusJ. 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.
113.
MeinsMLehmannJGerresheimF. 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.
114.
LugtenbergDde BrouwerAPKleefstraT. 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.
115.
SanlavilleDPrieurMde BloisMC. Functional disomy of the Xq28 chromosome region. Eur J Hum Genet. 2005;13(5):579–585.
116.
LahnBTMaNBregWR. Xq-yq interchange resulting in supernormal X-linked gene expression in severely retarded males with 46,XYq-karyotype. Nat Genet. 1994;8(3):243–250.
117.
LammerEJPungliaDRFuchsAE. Inherited duplication of Xq27.2→qter: phenocopy of infantile Prader-Willi syndrome. Clin Dysmorphol. 2001;10(2):141–144.
118.
GoodmanBKShafferLGRutbergJ. Inherited duplication Xq27-qter at Xp22.3 in severely affected males: molecular cytogenetic evaluation and clinical description in three unrelated families. Am J Med Genet. 1998;80(4):377–384.
119.
AkiyamaMKawameHOhashiH. Functional disomy for Xq26.3-qter in a boy with an unbalanced t(X;21)(q26.3;p11.2) translocation. Am J Med Genet. 2001;99(2):111–114.
120.
VasquezAIRiveraHBobadillaLCrollaJA. A familial xp+ chromosome, dup (Xq26.3→qter). J Med Genet. 1995;32(11):891–893.
121.
Kokalj-VokacNMarcun-VardaNZagoracA. Subterminal deletion/duplication event in an affected male due to maternal X chromosome pericentric inversion. Eur J Pediatr. 2004;163(11):658–663.
122.
NovelliABernardiniLSalpietroDC. Disomy of distal Xq in males: case report and overview. Am J Med Genet A. 2004;128(2):165–169.
