Abstract
Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient’s perspective and the appropriate treatment.
Highlights
Rett syndrome (OMIM#312750) is an early-onset neurodevelopmental disorder, which was first described by Doctor Andreas Rett in 1966 [1]
With whole-exome sequencing (WES) and panels that incorporate more and more genes related to the central nervous system, the number of patients with a pathogenic variant detected has increased in genes that were previously not related to Rett syndrome (RTT) nor RTT-like
All of the individuals summarized in this review met the diagnostic criteria for RTT or RTT-like; lacking a defect in methyl-CpG-binding protein 2 gene (MECP2) underscores the importance of carrying out additional genetic testing, whether it is by specific gene panels, WES or whole-genome sequencing (WGS), to identify the specific etiology and to direct appropriate diagnostic and therapeutic strategies
Summary
Rett syndrome (OMIM#312750) is an early-onset neurodevelopmental disorder, which was first described by Doctor Andreas Rett in 1966 [1]. It was not until 1999 when Zoghbi’s laboratory identified mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2; OMIM*300005) in RTT patients. The number of known genes which are disease-causing for RTT-like phenotypes increased remarkably in the last years. This development can be observed in the hugely heterogeneous group of neurodevelopmental disorders [10]. This study underlines the current molecular genetic studies performed in RTT patients, highlights the phenotype overlap with other monogenic disorders, and reviews the new treatments that are being performed
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