Medical Biases and Misconceptions Impact Diagnoses in Males With Loss of Function MECP2 Variants

Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. These variants were historically believed to be incompatible with life in males; however, recent advances in genetic testing have revealed significant clinical heterogeneity. The current study aimed to improve our understanding of diagnostic experiences in males with confirmed pathogenic alteration of MECP2. An international sample of caregivers completed a survey of diagnostic experiences (N = 47) and phenomenological interviews (n = 32). Median [interquartile range; IQR] age of genetic diagnosis was 3 years [1.08, 6.75]. Multivariate analysis showed that for every year increase in year of birth, age of diagnosis (in years) decreased by 0.31. Qualitative findings demonstrate that medical biases and widespread misconceptions contribute to delays in accurate clinical diagnosis, which negatively impacts child health and family functioning. As genetic testing becomes more widely available, age of genetic diagnosis is decreasing, resulting in more providers and families with unexpected results and a notable lack of male-specific anticipatory guidance and clinical recommendations. Diagnostic providers must increase their awareness of males with confirmed pathogenic alterations of MECP2 and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options.