Abstract
Purpose: To evaluate the phenotypes of individuals with pathogenic and likely pathogenic variants in the MECP2 gene.
Methods: We surveyed exome sequencing data from a large clinical care cohort for deleterious variation in the MECP2 gene. We reviewed de-identified clinical information for these individuals to interrogate for neurodevelopmental and neuropsychiatric phenotypes.
Results: We identified pathogenic and likely pathogenic variants in MECP2 in individuals with typical and atypical Rett syndrome, and neuropsychiatric phenotypes, and estimate a prevalence of MECP2-associated disorders of 1 in 2,645 individuals. We observed a 7.45x increased relative risk of neuropsychiatric phenotypes, especially major depression, in adult individuals with deleterious variants in MECP2 without a diagnosis of Rett syndrome. Male individuals with missense pathogenic variants in MECP2 appear to have more severe neuropsychiatric phenotypes.
Conclusions: We identified and report individuals with heterozygous pathogenic variants in MECP2 and their phenotypes in a large clinical cohort. The observed prevalence of MECP2-associated disorders in our cohort is higher than estimated in the literature. Individuals with pathogenic variants in MECP2 can survive into adulthood but are at increased risk of developing neuropsychiatric disorders, mainly major depression. Pathogenic variation in MECP2 is a likely important contributor to neuropsychiatric disorders in the general population.
Clinical Evaluation of Patients with Classical Rett Syndrome and MECP2 Gene Analysis
