mutation screening was reported for 2697 male individuals affected by a neurological disorder. In this heterogeneous population of patients, 46 potentially disease‐causing mutations were identified in different families and sporadic cases. They can be divided into two groups: 34 mutations that are certainly pathogenic (nonsense, frameshift and other mutations found in several girls with RS) and 12 unclassified variants consisting mainly of missense mutations found in a single family. The frequency of potentially disease‐causing MECP2
mutations in the population of mentally retarded male patients is thus between 1.3% and 1.7%. This is an important figure, considering that the incidence of fragile X syndrome, the most frequent familial cause of MR in males, is 2.8% in the same population.44
Five out of seven mutations identified by Del Gaudio et al29,33
are not taken into account in the numbers given above, as they were identified in a population of 1380 individuals whose phenotype and gender are not specified (these mutations are nonetheless listed in tables 1 and 2).
Many non‐pathogenic nucleotide changes were also identified in the MECP2
gene. This gene has a very high rate of de novo mutations, and several polymorphisms were found in affected and healthy individuals in the same family.45
These polymorphisms are not taken into account in the figures given here.
Frequencies can be calculated only if the number of screened patients is large enough. The first report of a large male population screened for mutations in MECP2
involved 185 mentally retarded patients negative for fragile X syndrome testing.12
In total, four (2.1%) mutations were reported as disease causing in this cohort. This surprisingly high figure prompted other laboratories to screen more similarly selected patients. However, the results showed a much lower incidence of mutations. In the subsequent reports involving a total of 829 patients,46,47
a single disease‐causing mutation was identified (0.1%). Hence, testing negative for the expansion of the FMR1 CGG repeat does not seem to be a very useful criterion to select a population for MECP2
After these misleading initial findings, subsequent screens were extended to include males affected by non‐specific MR. In the 658 patients reported to date,21,22,48,49,50,51,52
2 (0.3%) disease‐causing mutations were identified. The first mutation was present in a two‐generation family with three affected males,22
and the second in a male patient with unexplained MR.21
Targeted screens were also performed following the description of four patients with non‐specific MR and the A140V mutation,12,13
and five affected males in a single family with the psychosis, pyramidal signs and macro‐orchidism (PPM‐X) syndrome and the same A140V mutation.14
In total, 433 males with various forms of MR were screened for the presence of the A140V mutation,52,53
but no mutation was found, questioning the real frequency of this amino acid change in the mentally retarded male population.
Because of the partial phenotypic overlap between RS and patients having a defect of the 15q11q13 region causing Angelman or Prader–Willi syndrome (PWS),54,55
several studies tried to determine whether mutations could be found in MECP2
in patients negative for defects in this imprinted region. In a screen of 92 male patients negative for methylation defects at the UBE3A locus,39,52,56,57
mosaic mutation was found in just 1 (1.2%) patient.39
The patient in the report by Hitchins et al57
with the P56fs mutation had already been described twice.37,54
A G428S mutation described as pathogenic in such a patient56
was shown to be a rare non‐pathogenic variant.20
Because the patient reported by Kleefstra et al29
had a phenotype evocative of PWS, 71 male patients negative for PWS were also screened for MECP2
mutation but no mutation was identified.39,52
A cohort of 154 male autistic patients were screened, but no disease‐causing mutation, was found.58
More recently, large duplications involving the MECP2
locus were identified in 18 male patients with a severe neurological phenotype.30,31,32,33
These duplications represent 18 out of 34 (53%) of the currently known pathogenic mutations in this gene (18/34).