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No correlation between phenotype and genotype in boys with a truncating MECP2 mutation
  1. K Ravn1,
  2. J B Nielsen1,2,
  3. P Uldall3,
  4. F J Hansen3,
  5. M Schwartz1
  1. 1Department of Clinical Genetics, University Hospital, Rigshospitalet, Copenhagen, Denmark
  2. 2The John F Kennedy Institute, Gl Landevej 7, DK-2200 Glostrup, Denmark
  3. 3Department of Paediatrics, University Hospital, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to:
 Dr M Schwartz, Department of Clinical Genetics, Rigshospitalet 4062, Blegdamsvej 9, DK-2100 Copenhagen, Denmark;

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Rett syndrome (RS, MIM 312750) is an X linked dominant neurodevelopmental disorder, which has been considered to affect girls only.1 Males were thought to be aborted spontaneously or to have a different phenotype.2

The disease is caused by mutations in MECP2, encoding a methyl-CpG binding protein MeCP2.3 MeCP2 is an abundantly expressed protein acting as a global transcription repressor.4 The protein contains two domains, the 85 amino acid methyl-CpG binding domain (MBD) and the 102 amino acid transcriptional repression domain (TRD).4,5 Furthermore, a domain in the C terminal part of the protein, facilitating DNA binding and harbouring the nuclear localising signal (NLS), has been described.6

The mutation responsible for RS has now been found in the majority of RS patients and more than 100 different mutations have been published. Although some association between phenotype and genotype has been shown, their correlation is not predictive of the clinical manifestations in the individual case.7,8

Since 1999, when mutations in MECP2 were first reported in patients with RS,3 it has been possible to analyse boys for mutations resulting in a confirmation of the diagnosis in some of the earlier reported cases.9,10

Screening of groups of patients with mental retardation of different types has further identified MECP2 mutations in males. So far, 17 cases of males with a disease causing mutation in MECP2 have been found. However, six of them were found to have Klinefelter syndrome or were mosaics for the mutation in question.8–15 The latter can roughly be divided into two groups, the severe neonatal cases, who die within the first years of life, all caused by an MECP2 mutation that in females causes classical RS,8–10 and the non-specific mental retardation type with mutations that, if …

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