Rett Syndrome via the MECP2 Gene

Rett syndrome is a neurodevelopmental disorder that is one of the most frequent causes of intellectual disability in females. Rett syndrome patients display normal development during early infancy, but between 6 and 18 months undergo psychomotor regression in which they lose previously acquired skills (Neul et al. 2010. PubMed ID: 21154482). Other key features of Rett syndrome include language/communication dysfunction, microcephaly, stereotyped hand-wringing motions and seizures.

Variations of classic Rett syndrome, termed atypical Rett or Rett-like syndromes, have also been described. Atypical Rett syndome patients share major clinical features with classic Rett syndrome, but have variable secondary features such as bruxism, impaired sleep and growth retardation (Neul et al. 2010. PubMed ID: 21154482).

Rett syndrome is an X-linked dominant disorder. The majority of Rett cases are sporadic and are caused by de novo mutations in the MECP2 gene. Rett syndrome predominantly affects females. The penetrance of MECP2 pathogenic variants is variable due to biases in X-inactivation. Hemizygous causative variants in MECP2 were believed to be lethal in males. However, rare male patients with pathogenic variants in MECP2 have also been reported with non-syndromic intellectual disability, absence of speech, neurodevelopmental delay, and epilepsy (Campos et al. 2007. PubMed ID: 17084570; Schönewolf-Greulich et al. 2016. PubMed ID: 26936630).

MECP2 pathogenic variants associated with Rett syndrome include single nucleotide changes, large and small insertions or deletions and chromosomal rearrangements. Despite the wide array of causative variants, eight recurrent pathogenic variants in MECP2 (R106W, R133C, T158M, R168X, R255X, R270X R294X, R306C) account for ~60% of all Rett syndrome cases (Guerrini and Parrini. 2012. PubMed ID: 22998673).

Methyl CpG-binding protein 2 (MeCP2) is a transcriptional repressor. MeCP2 binds to methylated CpG dinucleotides and interacts with a variety of chromatin remodeling complexes to establish a silent chromatin state at the methylated gene. The MeCP2 protein is highly expressed in neurons, and MeCP2-dependent gene regulation is important for proper neuronal maturation (Na and Monteggia. 2011. PubMed ID: 20515694).

Causative point variants in MECP2 are found in 80% of typical Rett syndrome cases and 40% of atypical Rett syndrome cases (Christodoulou and Ho. 2012. PubMed ID:20301670).

This test provides full coverage of all coding exons of the MECP2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.