title: Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.
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.
authors.affiliation: 1] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA [2] Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Hodge
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mitchell
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Pillalamarri
authors.affiliation: Medical Genetics, MassGeneral Hospital for Children, Boston, MA, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Toler
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bartel
authors.affiliation: Fullerton Genetic Center, Mission Health, Asheville, NC, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Kearney
authors.affiliation: Clinical Cytogenetics Laboratory, Pathology Associates Medical Laboratories, Spokane, WA, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Zou
authors.affiliation: 1] Division of Genetics, Boston Children's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Tan
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hanscom
authors.affiliation: Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kirmani
authors.affiliation: Child Neurology, Department of Neurosciences, Mayo Clinic Health System, Eau Claire, WI, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Hanson
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Skinner
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Rogers
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Everman
authors.affiliation: Fullerton Genetic Center, Mission Health, Asheville, NC, USA.
authors.forename: E
authors.initials: E
authors.lastname: Boyd
authors.affiliation: Outpatient Behavioral Health, Agnesian Health Care, Fond Du Lac, WI, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tapp
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Mullegama
authors.affiliation: Department of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Keelean-Fuller
authors.affiliation: Department of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Powell
authors.affiliation: 1] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA [2] Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Elsea
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Departments of Obstetrics, Gynecology and Reproductive Biology and of Pathology, Brigham and Women's Hospital, Boston, MA, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Morton
authors.affiliation: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA [3] Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: B
authors.initials: B
authors.lastname: DuPont
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Chaubey
authors.affiliation: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Medical Genetics, MassGeneral Hospital for Children, Boston, MA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Lin
authors.affiliation: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA [3] Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D001007:Anxiety / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins; C550332:MBD5 protein, human