Scientists find mutations associated with unusual forms of Rett syndrome

An article published in the journal Human Genetics by Manel Esteller, Director of the Program for Epigenetics and Cancer Biology (PEBC) of Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics of the University of Barcelona, discovers mutations in genes associated with the development of atypical Rett syndrome, and distinguishes this clinical entity from other neurodevelopmental disorders of childhood. This study was made possible by the support received from the Catalan and Spanish Rett Syndrome associations, a crowdfunding campaign in Verkami and Finestrelles Foundation.

"We sequenced a total of 61 genomes corresponding to patients classified as atypical Rett syndrome and of their parents, who did not show any alteration in genes typically associated with this entity. This complex task of genomic analysis has allowed us to create a clearer picture of what is happening at the molecular level when atypical Rett Syndrome is diagnosed", says Dr. Manel Esteller. "Sometimes, the mutation responsible for Rett Syndrome is in one of the known genes, but it is located in a region not reached by the usual genetic analysis. Other patients sometimes show symptoms that look like an atypical Rett Syndrome, but mutations actually occur in other genes responsible for similar neurodevelopmental syndromes such as Dravet Syndrome, Pitt-Hopkins syndrome or monogenic diseases characterized by childhood epilepsy. "

"Finally, we have discovered two very interesting subgroups - explains the researcher -, girls who have mutations in new genes firstly associated with atypical Rett Syndrome, such as those found in synaptic neurotransmitter receptors; and the existence of patients, despite the detailed analysis of its genome, in whom we found no obvious mutation, which makes the existence of alternative non-genetic disease mechanisms possible."

Rett Syndrome is the second most common cause of intellectual disability in women after Down syndrome. The leading genetic cause of Rett Syndrome is the appearance of mutations in the MECP2 gene in the embryo, a regulator of expression of other genes in the genome. However, there are patients with classic Rett syndrome who do not have mutations in this gene symptoms, so they are diagnosed as atypical Rett Syndrome. Not knowing which gene or genes are responsible for the disease makes diagnosis, genetic counseling, monitoring and the possibility that patients can benefit from a future therapy difficult.

More information:

Lucariello M, Vidal E, Vidal S, Saez M, Roa L, Huertas D, Pineda M, Dalfó E, Dopazo J, Jurado P, Armstrong J, Esteller M. Whole exome sequencing of rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. Human Genetics, D

Image: Gene sequencing of a synaptic neurotransmitter receiver of an atypical Rett syndrome patient. The patient has a mutation at ''G'' nucleotide of DNA, marked with a blue line.