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Title: Genetic counselling in Rett syndrome. Part III. Phenotype-genotype correlation

Ewa Uścińska, Małgorzata Skawrońska, Alina T. Midro
Review articles
Pediatric Review
Start page:
Final page:
Rett syndrome, MECP2 gen, phenotype-genotype correlation, prognosis. met, vel ut deliquissim velis

Rett syndrome, one ofthe leading causes of developmental regression in girls, is connected with mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). The majority of mutations is due to C—>T transition at 5 '-CG-3' (CpG) sites in other disease genes, presumablyresultingfrom spontaneous deaminationofmethylatedcytosine. MeCP2 binds to methylatedDNA andmay regulate gene expression and modeling of chromatin struc ture. It is becoming evident that MeCP2, a protein originally thought of as a global transcriptional repressor, is actually specialized for a function in neurons of the central nervous system — expression ofa gene encoding BDNF. It has beenfound that the clinical phenotype can, at least in part, be explained in terms ofthe type and location ofthe MECP2 mutation and epigenetic factors such as skewing of X-chromosome inactivation. In addition to classicRTT, five distinct categories ofatypical cases have been delineated on the basis of clinical criteria. These variants have some, butnot all, diagnostic features of RTT and can be milder or more severe. Only the coding region has been thoroughly analyzed, however, so mutations in regulatory elements as well as in alternative splicingform couldaccount for those cases in which no mutation has been identified. Genotype/ phenotype analysis revealed that the phenotypic spectrum ofMECP2 mutations in humans is broader than initially suspected: mutations have been discoveredin Rett syndrome variants, mentally retardedmales, autistic children, Angelman likephenotype and Prader-Willy like phenotype. Some groups found thattruncating mutations leadtoamore severe overall phenotype than missense mutations, and thatlate truncations correlate with a less severe outcome than early truncations. Infemales with the preserved speech variant, all the mutations were eithermissense or late truncations, further supporting the notion that these types ofmutations have milder consequences than the early truncations seen in classic RTT. Several other studies, however, have found no significant correlation between the mutation type and the overallseverity of clinical features. This discordance likely resultsfrom thefact that thepattern of XCI can influence the phenotypic outcome ofmutations infemales.