title: Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.
abstract: Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Lucariello
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Servei de Medicina Genètica i Molecular, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues De Llobregat, Catalonia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vidal
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Saez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Roa
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain.
authors.forename: Dori
authors.initials: D
authors.lastname: Huertas
authors.affiliation: Fundació Hospital Sant Joan de Déu (HSJD), Barcelona, Catalonia, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Genetics Department, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Dalfó
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), 46012, Valencia, Spain.|Bioinformatics of Rare Diseases (BIER), CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.|Functional Genomics Node (INB) at CIPF, 46012, Valencia, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain. pjurado@idibell.cat.
authors.forename: Paola
authors.initials: P
authors.lastname: Jurado
authors.affiliation: Servei de Medicina Genètica i Molecular, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues De Llobregat, Catalonia, Spain. jarmstrong@hsjdbcn.org.|CIBER Enfermedades Raras, Barcelona, Catalonia, Spain. jarmstrong@hsjdbcn.org.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Catalonia, Spain. jarmstrong@hsjdbcn.org.
authors.forename: Judith
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. mesteller@idibell.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology
chemical_list: C000620754:ANKRD31 protein, human; C447158:CHRNA5 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human