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Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

Molecular Psychiatry volume 19, pages 368–379 (2014)Cite this article

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Abstract

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5′-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

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Acknowledgements

This work was funded by grants from the NIH GM061354 (CCM, JFG) and MH09586 (MET), and from the Fondation Jerome Lejeune (SHE). MET is also supported by the Simons Foundation for Autism Research, the Nancy Lurie Marks Family Foundation and NARSAD. We thank the patients and their families and physicians for participating in this study.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    J C Hodge & E Mitchell

  2. Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA

    J C Hodge & S Kirmani

  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    V Pillalamarri, C Hanscom, J F Gusella, A E Lin & M E Talkowski

  4. Medical Genetics, MassGeneral Hospital for Children, Boston, MA, USA

    T L Toler & A E Lin

  5. Greenwood Genetic Center, Greenwood, SC, USA

    F Bartel, S A Skinner, R C Rogers, D B Everman, B DuPont & A Chaubey

  6. Fullerton Genetic Center, Mission Health, Asheville, NC, USA

    H M Kearney & E Boyd

  7. Clinical Cytogenetics Laboratory, Pathology Associates Medical Laboratories, Spokane, WA, USA

    Y S Zou

  8. Division of Genetics, Boston Children’s Hospital, Boston, MA, USA

    W H Tan

  9. Harvard Medical School, Boston, MA, USA

    W H Tan & C C Morton

  10. Department of Neurosciences, Child Neurology, Mayo Clinic Health System, Eau Claire, WI, USA

    R R Hanson

  11. Outpatient Behavioral Health, Agnesian Health Care, Fond Du Lac, WI, USA

    C Tapp

  12. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    S V Mullegama & S H Elsea

  13. Department of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    D Keelean-Fuller & C M Powell

  14. Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    S H Elsea

  15. Departments of Obstetrics, Gynecology and Reproductive Biology and of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    C C Morton

  16. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    C C Morton, J F Gusella & M E Talkowski

  17. Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA

    J F Gusella & M E Talkowski

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  1. J C Hodge
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  2. E Mitchell
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  3. V Pillalamarri
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Correspondence to J C Hodge or M E Talkowski.

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Hodge, J., Mitchell, E., Pillalamarri, V. et al. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry 19, 368–379 (2014). https://doi.org/10.1038/mp.2013.42

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