Spectrum of MECP2 mutations in Rett syndrome.

Mutations in the methyl-CpG-binding protein 2 gene (MECP2) are identified in the majority of females with Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder. We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases, we here present 18 additional mutations. We found 13 single nucleotide substitutions, all of which are C-->T transitions at CpG hot spots. Frameshift mutations, leading to premature termination of translation, include two single guanine (G) nucleotide deletions from a stretch of contiguous Gs, a novel four nucleotide deletion, a novel 32 nucleotide deletion in the C-terminal domain and a novel complex duplication/deletion rearrangement in the same region. When X-chromosome inactivation patterns were compared in 16 MECP2 mutation-positive and 23 mutation-negative samples, no significant differences were observed. The mutational spectrum in our subject population is similar to studies from around the world. Of over 300 MECP2 mutations reported, two-thirds are truncating mutations and one-third are missense mutations, mostly in the methyl-binding domain. Nearly 70% of all identified mutations are C-->T transitions at one of eight CpG hot spots, and about 10% are intragenic deletions or complex rearrangements that lead to frameshifts in the C-terminal region. The rate of mutation detection in the MECP2 coding region ranges from 70 to 85% in clinically diagnosed RTT and is much lower in diagnostic variants.