Caracterización clínica y molecular del síndrome de Rett: elucidar los casos no resueltos

Abstract

El objetivo principal de la presente tesis doctoral es la mejora en el diagnóstico genético y la posibilidad de dar un pronóstico sobre desarrollo de la enfermedad en pacientes con RTT/RTT-like. Asimismo, profundizar en el estudio de pacientes sin diagnóstico genético para poder determinar la etiología de su clínica.

Los objetivos concretos son:

1. Análisis de variantes en genes relacionados con la clínica RTT y RTT-like en una amplia serie de pacientes analizados mediante NGS: valorar las distintas metodologías usadas para el diagnóstico molecular e identificar las causas que puedan explicar el fenotipo de las pacientes tanto en genes conocidos como en genes nuevos.

2. Caracterización clínica y molecular de pacientes con grandes deleciones en MECP2: Análisis en profundidad de los mecanismos que conducen a los grandes reordenamientos en MECP2 e intentar determinar una correlación entre los tamaños de las deleciones y la clínica que desarrollan las pacientes.

3. Análisis de correlaciones genotipo-fenotipo entre RTT y RTT-like: estudio de los genes alterados asociados a otras patologías para establecer una posible relación entre pacientes RTT y RTT-like, así como estudiar las vías que puedan conectar a los nuevos genes asociados con clínica RTT-like a las vías asociadas a MECP2.

4. Caracterización funcional de los hallazgos detectados por NGS de mutaciones en genes sin asociación fenotípica que pudieran explicar la clínica de las pacientes.

Rett syndrome is a genetically based neurodevelopmental disorder that is included in the rare disease group due to its low incidence in the population. However, this disease is the second cause of severe intellectual disability in women after Down syndrome. This disorder was first described in 1966 by Dr. Andreas Rett, although it was not until 1963 that the Swedish pediatrician Hagberg defined it as Rett syndrome. Nevertheless, it was not until 20 years after the genetic cause behind the syndrome, the MECP2 gene malfunction, was clarified. This finding allowed the genetic diagnosis in a large part of patients with a clinical diagnosis of RTT. However, approximately 5% of patients with classic RTT and more than 25% of patients with atypical forms present negative results for mutations in the MEPC2 gene. This led to the search for other possible genes involved in RTT, especially in the case of atypical forms. Subsequent studies in search of a genetic cause for those patients without diagnosis made it possible to link the CDKL5 and FOXG1 genes to this pathology in 2004 and 2008, respectively. Even so, there is a percentage of patients with the Rett phenotype or similar that their ethology still remains unknown. Recently, next generation sequencing has promoted genetic diagnoses because of the quickness and afford ability of the method. Thus, the introduction of these new technologies allowed us to study a larger number of genes associated with RTT or similar phenotypes simultaneously, providing a genetic diagnosis for a wider group of patients. These new findings allow us to provide the clinician with more information and clues that could help in the prevention of future symptoms or in pharmacologic therapy. Likewise, these results have allowed us to understand the complexity of the disorder a little better.