Rett syndrome (RTT; MIM 312750) is a neurodevelopmental disorder with an onset in early childhood that affects 1/10 000–1/15 000 females. After a period of relatively normal development, girls with RTT present with developmental arrest, usually by 12–18 months of age, followed by rapid deterioration with regression of speech and purposeful hand movements. Girls loose acquired communication skills coincident with the appearance of autistic features, deceleration of head growth, seizures, ataxia, awake respiratory dysfunction, and stereotypic hand movements.¹

RTT is caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MECP2; MIM 300005).² The involvement of MeCP2 in methylation specific transcriptional repression suggests that the symptoms of RTT are the consequence of inappropriate transcription of genes important for neuronal function and brain development. PCR amplification followed by direct sequencing of MECP2 coding exons 2 through 4 has become the standard diagnostic approach for clinically suspected RTT, but mutations are detected in only ∼85% of individuals with classic RTT.^3,4 Gene dosage analysis by Southern hybridisation or multiplex ligation dependent probe amplification has resulted in identification of large genomic deletions of the MECP2 genomic locus in an additional subset of these mutation negative RTT patients.^5–7 However, the causative mutation is still unknown in the remaining 5–10%.

It has recently been discovered that MECP2 has two splice variants encoding two protein isoforms that differ in their N terminus.^8,9 The previously known mRNA splice variant (NM_004992) encodes a less abundant protein that is 12 amino acids shorter and translated from an ATG initiation codon in exon 2. The newly recognised transcript (AY541280) excludes exon 2 and encodes a longer protein translated from an ATG in exon 1, which was previously thought to be a non-coding exon.^8,9 According to recently agreed nomenclature (Rett …