Overview of MECP2 mutations identified in individuals referred for Rett syndrome, variant Rett syndrome and X-linked MR
Rett syndrome is an X-linked dominant progressive neurological disorder affecting primarily females. Approximately 96% of females with classic Rett syndrome and 50% of those with variant Rett syndrome have mutations in the MECP2 gene. In males, mutations in MECP2 are associated with neonatal encephalopathy, variant Rett syndrome and X-linked recessive mental retardation (MR).
Our mutation analysis of MECP2 is done for both female and male patients with symptoms of classic or variant Rett syndrome as well as X-linked MR. It consists of sequencing exons 2, 3 and 4 of the MECP2 gene. Large deletions and duplications are detected using multiplex ligation-dependant probe amplification (MLPA). Carrier mothers are further investigated for skewed X-inactivation.
To date, a total of 258 probands have been analyzed (208 females and 50 males). Previously reported mutations were identified in 39 (15%) of probands (37 females (18%) and 2 males (4%)). Ten novel mutations (3 frameshift and 7 missense) were also characterized. Of the seven missense mutations, two are likely disease causing; two are likely polymorphisms and the remaining three are unknown variants. Specifically, the p.Pro388Ala mutation was found in the proband’s mother. She also showed skewed X-inactivation indicating she could be a carrier. The p.Tyr141Ser mutation was not found in the proband’s mother, however the father has not been tested, therefore we do not know if it was de novo in the proband. The p.Arg190Cys mutation was identified in a male with MR. Both the mother and maternal grandmother were found to be carriers but did not demonstrate skewed X-inactivation. Therefore, it is possible that this mutation results in X-linked recessive MR.
In conclusion, a total of 44 (17%) probands (42 females (20%); 2 males (4%)) were identified as having mutations contributing to their phenotype. Among the ten novel mutations, five are disease-related, two are polymorphisms and three are of unknown cause.