02967nas a2200529 4500008004100000022001400041245011800055210006900173260001200242300001400254490000800268520135400276653001501630653001001645653001201655653002701667653002101694653002401715653001001739653002101749653002801770653001001798653001101808653003501819653002201854653004201876653001101918653003301929653001301962653002601975653003702001653002502038653001802063100002202081700001902103700001802122700001902140700001502159700001802174700001902192700001902211700002002230700001802250700002202268700002002290856012702310 2016 eng d a1432-120300aWhole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.0 aWhole exome sequencing of Rett syndromelike patients reveals the c2016 12 a1343-13540 v1353 a
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.
10aAdolescent10aAdult10aAnimals10aCaenorhabditis elegans10aCarrier Proteins10aCell Cycle Proteins10aChild10aChild, Preschool10aDNA Mutational Analysis10aExome10aFemale10aForkhead Transcription Factors10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aHumans10aMethyl-CpG-Binding Protein 210amutation10aNerve Tissue Proteins10aProtein Serine-Threonine Kinases10aReceptors, Nicotinic10aRett Syndrome1 aLucariello, Mario1 aVidal, Enrique1 aVidal, Silvia1 aSaez, Mauricio1 aRoa, Laura1 aHuertas, Dori1 aPineda, Mercè1 aDalfó, Esther1 aDopazo, Joaquin1 aJurado, Paola1 aArmstrong, Judith1 aEsteller, Manel uhttps://www.clinbioinfosspa.es/content/whole-exome-sequencing-rett-syndrome-patients-reveals-mutational-diversity-clinical