Developmental delay and the methyl binding genes.

The report by Amir et al 1 that Rett syndrome (RS) is associated with mutations in the MECP2 gene permitted laboratory diagnosis of this devastating yet common neurodevelopmental disorder. Hitherto the paucity of familial cases of the syndrome and the failure to identify the syndrome in males despite fairly wide clinical criteria had defined it as an X linked dominant disorder with male lethality. Soon, however, reports from the few families in which RS is segregating showed that male family members who inherited the same mutation in the MECP2 gene as their affected female relatives did sometimes survive to birth and beyond, but they did not, as the females did, develop Rett syndrome but were subject to an entirely different syndrome of severe male encephalopathy. 4 In the meantime, attempts were being made to relate the severity of the clinical picture presented by girls with RS (ranging from “classical” to “forme fruste”) with the individual mutations. No correlations were observed either with the type of mutation or with its position within the MECP2 gene save that N-terminal changes tended to be more severe than those located further downstream. The gene is divided into a methyl binding domain (MBD), a transcription repression domain (TRD), and a proline rich C-terminal domain. Mutations cause loss of function by interfering either with DNA binding or with the downstream association of MeCP2 with its transcriptional corepressors Sin3A and HDAC. To date, >200 different mutations have been detected in girls with RS, >95% are de novo, and they are found in all of the domains. Those in the MBD are predominantly missense while those in the TRD tend to be nonsense or truncating mutations. Downstream C-terminal mutations may be individual and are often of the insertion or deletion type. Despite the wide range of changes reported, it has been suggested that >60% are the result of R106W and T158M (in the MBD), R168X (between the MBD and the TRD), and R255X, R270X and R294X (in the TRD). Studies on other types of developmental delay, both familial and de novo, have indicated that mutations in the MECP2 gene may be more common and related to more types of handicap than had previously been anticipated. Two studies of children referred with a clinical diagnosis of Angelman syndrome (AS) but without an abnormality in 15q11q13 showed that 4/46 of the girls in one case and 5/40 in the other actually had Rett syndrome. Of these nine probands, only one was later found to have a clinical presentation inconsistent with the laboratory diagnosis. This may not be surprising given that in very small girls the two syndromes may present with overlapping clinical features and so be difficult to differentiate on clinical grounds alone. Familial cases of developmental handicap indicate that males often show changes in the MECP2 gene which would normally be considered to be SNPs and so unrelated to the clinical symptoms. Females in these families who are carriers of such changes are nearly always unaffected or very mildly so, most probably because of the effect of X inactivation. Thus, females with mutations in the MECP2 gene which affect the function of the MeCP2 protein may develop RS or other forms of severe developmental delay. Males with this type of mutation will, if they survive to birth, develop lethal encephalopathy. If the mutation in males is in mosaic form or is located within an XXY genotype, then classical Rett syndrome may result. 12 13 In addition, a series of “milder” changes which would certainly not be expected to affect gene function markedly, if at all, in heterozygous females, may in the hemizygous male be associated with a milder disorder (table 1). Although mutations in the MECP2 gene account for >90% of Rett syndrome, in view of the range of clinical severity, there may be a significant minority of cases of “atypical” disorder or other types of developmental delay which are related to the other methyl binding proteins MBD1 and MBD2. Both MBD1 and MBD2, which is a component of the MeCP1 complex, are, like MeCP2, able to repress transcription by binding to methylated CpG. We therefore attempted to answer the following questions concerning the relationship between changes in the MECP2 gene and developmental delay. How many children of either sex referred for molecular testing for AS but with no detectable molecular changes in 15q11q13 have mutations in