Abstract
Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.
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Acknowledgements
We thank the patients and their family for their kind cooperation. We thank the cytogenetics and molecular genetics staff at the Nancy Univesity Hospitals for their expert technical assistance. This study was supported by grants from the French Ministry of Health (DGOS) and the ‘Fondation Jérôme Lejeune’.
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Bonnet, C., Ali Khan, A., Bresso, E. et al. Extended spectrum of MBD5 mutations in neurodevelopmental disorders. Eur J Hum Genet 21, 1457–1461 (2013). https://doi.org/10.1038/ejhg.2013.22
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DOI: https://doi.org/10.1038/ejhg.2013.22
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