Submission Details

MECP2 was discovered as the causative gene of Rett syndrome in 1999, and since then over 4,600 MECP2 variants have been identified (Wan et al. 1999, Bienvenu et al. 2000, Krishnaraj et al. 2017). MECP2-associated Rett syndrome is an X-linked dominant disease affecting primarily females. Rett syndrome is characterized by normal development during the first 6-18 months of life followed by a phase of rapid regression in language and motor skills followed by long-term stability. Other features include stereotypic hand movements, fits of screaming and crying, autistic features, panic-like attacks, bruxism, apnea, gait ataxia, tremors, seizures, and acquired microcephaly. The majority of MECP2 variants arise de novo, however some instances of maternal germline mosaicism have been described (Amir et al. 1999, Venancio et al. 2007). The majority of de novo variants are paternal in origin (Zhang 2012), and in such families only females would be affected. However, some males hemizygous for MECP2 variants are viable and have severe neonatal encephalopathy and intellectual disability. Many mouse models of MECP2-deficiency have phenotypic features consistent with Rett syndrome (Chen et al. 2001, Guy et al. 2001, Shahbazian et al. 2002, Guy et al. 2007, McGraw et al. 2011). In summary, MECP2 is definitively associated with Rett syndrome in an X-linked dominant manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1497/)