Rett syndrome is caused by pathogenic variants in the MECP2 gene on the X chromosome. The ClinGen evidence supporting MECP2 as the cause of Rett syndrome is classified as definitive. Most cases arise from de novo pathogenic variants, meaning the genetic change occurred in the egg, sperm, or very early embryo and is not inherited from either parent; according to the available data, more than 99 percent of cases are de novo, so there is usually no prior family history. Rett syndrome is inherited in an X-linked dominant pattern. Because MECP2 is on the X chromosome, females, who have two X chromosomes, may have variable presentations depending on the pattern of X-chromosome inactivation: according to expert review, females with favorably skewed X-inactivation may have milder manifestations or, rarely, no observable features at all, while most affected females have the classic phenotype. Males with classic MECP2 loss-of-function variants are typically severely affected or do not survive infancy, although some males have a milder MECP2-related phenotype with different variants. In rare situations, a parent may carry the variant only in their reproductive cells (germline mosaicism), which can produce familial recurrence even when blood testing of parents is negative. Recurrence risk for siblings is low overall but not zero, and genetic counseling is recommended for affected families to discuss inheritance, recurrence risk, and family planning options.

Diagnosis of Rett syndrome is initially clinical, based on the characteristic developmental course and the presence of defining features such as developmental regression, loss of purposeful hand use, hand stereotypies, and gait abnormalities. Clinical diagnostic criteria have been established and are used by experienced neurologists and geneticists. MECP2 gene sequencing identifies a pathogenic variant in approximately 95 percent of individuals with classic Rett syndrome, and deletion or duplication analysis is performed when sequencing is negative. For atypical presentations, additional testing for related conditions may be considered when MECP2 testing is negative, since several other neurodevelopmental disorders can mimic Rett syndrome, particularly in early stages. Many of the early features of Rett syndrome can also be seen in other neurodevelopmental conditions, so molecular genetic testing is essential to confirm the diagnosis and to distinguish Rett syndrome from conditions with similar presentations.

Care for Rett syndrome is built on a foundation of comprehensive supportive management, with a targeted medication available for eligible individuals. Foundational care includes seizure management with antiepileptic medications when seizures occur, physical therapy to maintain mobility and prevent contractures, speech-language therapy with augmentative and alternative communication strategies, occupational therapy aimed at supporting hand function and daily living skills, nutritional and feeding support, and management of breathing abnormalities and sleep disturbances. Regular surveillance is an essential part of long-term care, helping to identify potential complications such as scoliosis, gastrointestinal issues, and changes in cardiac or respiratory function before they become serious. DAYBUE (trofinetide) and DAYBUE STIX are FDA-approved for the treatment of Rett syndrome in adults and children two years of age and older. Trofinetide may lead to modest improvements in some neurological symptoms in certain individuals; response varies, and long-term outcomes continue to be studied. Eligibility for trofinetide depends on individual factors that are best discussed with the care team, including age, weight, and other clinical considerations. Care is most effective when delivered through a multidisciplinary team that typically includes a neurologist, developmental pediatrician, geneticist, genetic counselor, physical therapist, speech-language pathologist, and pulmonologist, with input from orthopedics and other specialties as needed. Patient assistance programs may be available to help cover treatment costs. Patients should discuss treatment options with their healthcare team to determine which therapies may be appropriate for their specific situation, and genetic counseling is recommended.

Rett syndrome is a lifelong neurodevelopmental condition characterized by an initial regression, followed by a period of relative stabilization and, in some individuals, later motor decline. The course is not uniformly progressive, and many individuals stabilize after the regression phase and live into adulthood, with quality of life that depends heavily on the consistency of multidisciplinary care, communication support, and family and community engagement. With current standards of care, including comprehensive supportive care, attention to seizure management, respiratory and cardiac monitoring, and the more recent availability of a targeted medication, outcomes have improved compared with older medical literature. Outcomes depend on a range of factors, including the specific MECP2 variant, the pattern of X-inactivation, the presence and management of seizures, respiratory and cardiac surveillance, nutritional status, and access to specialty care. Connection with a specialty Rett syndrome center, a genetic counselor, and a patient organization is among the most reliable ways for families to stay current with rapidly evolving options.

Rett syndrome is an active research area with several ongoing clinical trials investigating new treatment approaches. Major directions include gene therapy programs aimed at delivering a working copy of MECP2, MECP2 reactivation strategies (because females have one normal copy of MECP2 that is often silenced by X-inactivation), additional targeted therapies that build on the trofinetide pathway, and improved tools for measuring response. Patient organizations maintain disease registries that help researchers understand the natural history of Rett syndrome and connect families to studies for which they may be eligible. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility, since eligibility often depends on age, the specific MECP2 variant, current functional status, and prior treatment history.