X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients
Authors: Xiol Clara , Vidal Silvia , Pascual-Alonso Ainhoa , Blasco Laura , Brandi Núria , Pacheco Paola , Gerotina Edgar , O’Callaghan Mar , Pineda Mercè , Armstrong Judith ,   Rett Working Group, Aguirre Francisco Javier , Aleu Montserrat , Alonso Xènia , Alsius Mercè , Amorós Maria Inmaculada , Antiñolo Guillermo , Aquino Lourdes , Arellano Carmen , Arriola Gema , Arteaga Rosa , Baena Neus , Barcos Montserrat , Belzunces Nuria , Boronat Susana , Camacho Tomás , Campistol Jaume , Campo Miguel del , Campo Andrea , Cancho Ramon , Candau Ramon , Canós Ignacio , Carrascosa María del Carmen , Carratalá-Marco Francisco , Casano Jovaní , Castro Pedro , Cobo Ana , Colomer Jaime , Conejo David , Corrales Maria José , Cortés Rocío , Cruz Gabriel , Csányi Gábor , Santos María Teresa de , Toledo María de , Campo Miguel Del , Toro Mireia Del , Domingo Rosario , Duat Anna , Duque Rosario , Esparza Ana María , Fernández Rosa , Fons Maria Carme , Fontalba Ana , Galán Enrique , Gallano Pia , Gamundi María José , García Pedro Luis , García María del Mar , García-Barcina María , Garcia-Catalan María Jesús , García-Cazorla Ángels , García-Miñaur Sixto , Garcia-Peñas Juan Jose , García-Silva María Teresa , Gassio Rosa , Geán Esther , Gil Belén , Gökben Sarenur , Gonzalez Luis , Gonzalez Veronica , Gonzalez Julieta , González Gloria , Guillén Encarna , Guitart Miriam , Guitet Montserrat , Gutierrez Juan Manuel , Gutiérrez Eva , Herranz Jose Luís , Iglesias Gemma , Karacic Iva , Lahoz Carlos H. , Lao José Ignacio , Lapunzina Pablo , Lautre-Ecenarro María Jesús , Lluch María Dolores , López Laura , López-Ariztegui Asunción , Macaya Alfons , Marín Rosario , Marquez Charles M. Lourenço , Martín Elena , Martínez Beatriz , Martínez-Salcedo Eduardo , Mas María José , Mateo Gonzalo , Mendez Pilar , Jimenez Amparo Morant , Moreno Sira , Mulas Fernando , Narbona Juan , Nascimento Andrés , Nieto Manuel , Nunes Tania Fabiola , Núñez Núria , Obón María , Onsurbe Ignacio , Ortez Carlos Ignacio , Orts Emilio , Martinez Francisco , Parrilla Rafael , Pascual Samuel Ignacio , Patiño Ana , Pérez-Poyato Maria , Pérez-Dueñas Belén , Póo Pilar , Puche Eliodoro , Ramos Feliciano , Raspall Miquel , Roche Ana , Roldan Susana , Rosell Jordi , Ruiz Cesar , Ruiz-Falcó María Luz , Russi Maria Eugenia , Samarra Jordi , Antonio Victoria San , Sanchez Ivan , Sanmartin Xavier , Sans Ana , Santacana Alfredo , Scholl-Bürgi Sabine , Serrano Nuria , Serrano Mercedes , Martin-Tamayo Pilar , Tendero Adrián , Torrents Jaime , Tortosa Diego , Triviño Emma , Troncoso Ledia , Turón Eulàlia , Vázquez Pilar , Vázquez Carlos , Velázquez Ramón , Ventura Clara , Verdú Alfonso , Vernet Anna , Vila M. Tomás , Villar Cristina 
Published: August 2019

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.