Genetics and Inheritance

Genetics of Rett Syndrome

The vast majority of cases of classic Rett syndrome are caused by mutations in the MECP2 gene. This gene, located in the Xq28 region, provides instructions for producing a protein (MeCP2) that is important for normal brain development and function. MeCP2 protein has several functions, including regulating other genes in the brain and maintaining connections (synapses) between nerve cells.

Using a battery of modern mutation detection assays, mutations in MECP2 can be found in 95–97% of individuals with typical RTT. Genotype-phenotype correlation studies have so far yielded inconsistent results.

Mutations in the CDKL5 gene, located in the Xp22 region, cause the early-onset seizure variant of Rett syndrome. The CDKL5 gene codes for a protein that is involved in brain development and appears to be essential for normal brain function. Although little is known about the protein's function, it may play a role in regulating the activity of other genes, including the MECP2 gene.

The congenital variant of Rett syndrome is caused by mutations in the FOXG1 gene, located in 14q12. The protein produced from this gene regulates several other genes involved in brain development.

 

Inheritance of Rett Syndrome

The MECP2 gene (as well as the CDKL5 gene) is located on the X chromosome.

MECP2 (and CDKL5)-related disorders are inherited in an X-linked dominant fashion (X-linked dominant is a dominant trait or disorder caused by a mutation in a gene on the X chromosome; in this case the phenotype is expressed in heterozygous females as well as in hemizygous males-having only one X chromosome but generally affected males tend to have a more severe phenotype than affected females).

Approximately 99.5% of RS are isolated cases within a family, occurring because of a de novo mutation within the child otherwise in the minority of cases from inheritance from a parent who has germ cell or somatic mosaicism. Families of girls with RS should be referred for genetic counseling to discuss recurrence and prenatal testing options.