Journal
HUMAN GENETICS
Volume 135, Issue 12, Pages 1343-1354Publisher
SPRINGER
DOI: 10.1007/s00439-016-1721-3
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Funding
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7 under REA of the EPITRAIN project [PITN-GA-2012-316758]
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7 under REA of DISCHROM [PITN-GA-2009-238242]
- E-RARE EuroRETT network (Carlos III Health Institute) [PI071327]
- Foundation Lejeune (France)
- Cellex Foundation
- Boton Foundation
- Finestrelles Foundation
- Catalan Association for Rett Syndrome
- Health Department of the Catalan government (Generalitat de Catalunya)
- Science Department of the Catalan government (Generalitat de Catalunya)
- ICREA Funding Source: Custom
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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.
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