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Genomic analyses in a large clinical cohort reveal high prevalence of MECP2 variants associated with neuropsychiatric phenotypes in adulthood

By Claudia Gonzaga-Jauregui, Alina Kurolap, Lauren Walsh, Jeffrey Staples, Cristopher Van Hout, Matthew Oetjens, Daren Liu, Regeneron Genetics Center, Rodney Samaco, Karin Weiss, Hagit Baris Feldman, Christa L Martin

Posted 04 Jun 2021
medRxiv DOI: 10.1101/2021.05.31.21257498

PurposeTo evaluate the phenotypes of individuals with pathogenic and likely pathogenic variants in the MECP2 gene. MethodsWe 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. ResultsWe 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. ConclusionsWe 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.

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