Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Article abstract-Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Methods: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Results: Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3Ј untranslated region (UTR), and represents the first report of involvement of the 3Ј UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter's male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(del32)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. Conclusion: This patient series confirms the high frequency of MeCP2 gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).

The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the child neurologist.

No abstract