The continuing Conundrum regarding MECP2 variants in Males |Biomedgrid

Rett syndrome (RTT) was first recognized by Andreas Rett nearly sixty years ago [1] and came to international attention following the landmark publication of Hagberg et al. in 1983 [2]. Subsequent studies sought to identify the molecular underpinnings of this rare neurodevelopmental disorder as a genetic etiology seemed to be the most likely mechanism regarding its causation. In 1999, Amir et al. established that RTT is caused by variants in the methyl-CpG-binding protein 2 (MECP2) gene located a Xq28 [3]. At present, more than 96% of individuals fulfilling the diagnostic criteria for RTT have a variant in this gene [4]. As an X-linked dominant disorder, its occurrence solely in females was expected and the presence of MECP2 variants in males was initially regarded as lethal. Subsequently, numerous reports emerged in the decade after the gene discovery describing males with MECP2 variants and clinical features ranging from developmental delay to significant neonatal encephalopathy [5-19]. Yet, the notion that pre-term or early neonatal male lethality is likely has remained even to the present day [20], plus two reports from rettsyndromenews. com/2021/12/15 and rettsyndromenews.com/2022/05/25. Adding to the confusion, the presence of classic RTT in males with MECP2 variants and X-chromosome mosaicism is well-documented, either due to somatic mosaicism or in association with Klinefelter syndrome, a 47XXY chromosomal disorder.