Rett Syndrome: Genetics

Classic Rett syndrome, due to mutations in the MECP2 gene, is a clinical diagnosis in girls who have developmental regression, loss of purposeful hand movements, hand stereotypies, and seizures. The range for clinical problems due to MECP2 mutations has been found to be much broader than classic RS, from severe neonatal encephalopathy in males to mild learning problems in females.
Approximately 80% of girls with the clinical diagnosis of RS are found to be MECP2 mutation positive through gene testing by sequence analysis/ mutation scanning and deletion. Mutation negative results in a girl with classic RS are probably due to mutations in untranslated sections of the gene that are not currently tested – banking blood for future testing may be of value.
The MECP2 gene is on the X chromosome and MECP2-related disorders are inherited in an X-linked dominant fashion. MECP2 is methyl-CpG binding protein 2 and is thought to be a global transcriptional repressor, involved in regulation of DNA expression in all tissues. It is not understood why a protein that is in all tissues is involved in a disease where the manifestations are primarily neurologic. The function of MECP2 in the human brain is also not well understood, but it is thought to be involved with development of the cortex in late infancy.
Approximately 99.5% are isolated cases of RS within a family, occurring either because of a de novo mutation within the child or 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; there are certain situations where the risk may be as high as 50% (e.g., if the mother also has the MECP2 mutation).
Attempts at phenotype-genotype correlation have not been very helpful in predicting the severity of RS. [Matijevic: 2009]
Males with MECP2 mutations have severe neonatal encephalopathy and respiratory abnormalities and are thought to be under-reported, since few physicians will think of MECP2 testing for very sick newborns. Males with 47, XXY karyotypes may meet the criteria for RS, as may males with post-zygotic MECP2 mutations resulting in somatic mosaicism. MECP2 is also thought to be responsible for syndromic and non-syndromic inherited mental retardation and possibly a syndrome of mild learning disabilities in females.
Please see MECP2-Related Disorders (GeneReviews) for detailed information on Rett syndrome genetics and Rett syndrome (GeneTests) for laboratories providing genetic testing.


Information & Support

For Professionals

MECP2-Related Disorders (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

For Parents and Patients

Rett Syndrome (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.


Pediatric Genetic Counseling

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Pediatric Genetics

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Author: Lynne M. Kerr, MD, PhD - 1/2009
Reviewing Author: Karin Dent, MS, CGC - 1/2009

Page Bibliography

Matijevic T, Knezevic J, Slavica M, Pavelic J.
Rett syndrome: from the gene to the disease.
Eur Neurol. 2009;61(1):3-10. PubMed abstract