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Novel variants identified in methyl-CpG-binding domain genes in autistic individuals

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Abstract

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family.

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Acknowledgements

We are grateful to the patients with autism and their families for their participation, without whom, this work would not be possible. A subset of the participants was ascertained while several of the authors (RR, IK, MYR, ERM, MLC, MAPV, and JRG) were at Duke University. We also acknowledge fellow lab members for their critical review of this manuscript. This research was supported by grants from the National Institutes of Health (NS26630, NS36768, and MH080647), Autism Speaks, and by a gift from the Hussman Foundation. RR is supported by the Ramon y Cajal program.

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Correspondence to John R. Gilbert.

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Supplementary Table 1

Primers designed for MBD exonic amplification (XLS 41 kb)

Supplementary Table 2

Population frequencies from dbSNP (XLS 31 kb)

Supplementary Table 3

Primers designed for MBD exonic amplification (XLSX 13 kb)

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Cukier, H.N., Rabionet, R., Konidari, I. et al. Novel variants identified in methyl-CpG-binding domain genes in autistic individuals. Neurogenetics 11, 291–303 (2010). https://doi.org/10.1007/s10048-009-0228-7

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