Cited by 249Genomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental DisordersGenomics and Rare Diseases

Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder

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Talkowski, Michael E., Mullegama, Sureni V., Rosenfeld, Jill A., van Bon, Bregje W.M., Shen, Yiping, Repnikova, Elena A., Gastier-Foster, Julie, Thrush, Devon Lamb +27 more·2011·The American Journal of Human Genetics

Abstract

Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.

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Crossref · 10.1016/j.ajhg.2011.09.011

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Authors
Talkowski, M. E., Mullegama, S. V., Rosenfeld, J. A., van Bon, B. W. M., Shen, Y., Repnikova, E. A., Gastier-Foster, J., Thrush, D. L., Kathiresan, S., Ruderfer, D. M., Chiang, C., Hanscom, C., Ernst, C., Lindgren, A. M., Morton, C. C., An, Y., Astbury, C., Brueton, L. A., Lichtenbelt, K. D., Ades, L. C., Fichera, M., Romano, C., Innis, J. W., Williams, C. A., Bartholomew, D., Van Allen, M. I., Parikh, A., Zhang, L., Wu, B.-L., Pyatt, R. E., Schwartz, S., Shaffer, L. G., de Vries, B. B. A., Gusella, J. F., & Elsea, S. H.
Affiliations
  • Broad Institute (US)
  • Virginia Commonwealth University (US)
  • PerkinElmer (United States) (US)
  • Boston Children's Hospital (US)
  • Nationwide Children's Hospital (US)
  • Massachusetts General Hospital (US)
  • Brigham and Women's Hospital (US)
  • Fudan University (CN)
  • Birmingham Women's Hospital (GB)
  • University Medical Center Utrecht (NL)
  • Oasi Maria SS (IT)
  • University of Michigan (US)
  • University of Florida Health (US)
  • Case Western Reserve University (US)
  • LabCorp (United States) (US)
Corresponding author
Elsea, Sarah H.
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2011-10
Volume
89
Issue
4
Pages
551-563
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2134256373
Cited by
249
References
50
Citations by year
2026: 4 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 14 · 2021: 13 · 2020: 13 · 2019: 14 · 2018: 42 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 24 · 2013: 28 · 2012: 25
FWCI
15.73
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
  • National Institutes of Health (1rc2hl103010-01)
  • National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
  • National Institute of Mental Health (F32MH087123)
  • National Institute of General Medical Sciences (GM061354, P01GM061354)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065286, R21HD065286)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
MBD5, intellectual disability, epilepsy, autism spectrum disorder, haploinsufficiency, chromosomal microdeletion, translocation breakpoints, gene expression, missense mutations, genetic risk, chromatin remodeling, epigenetic regulation
MeSH terms
Adolescent, Adult, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 2, DNA-Binding Proteins, Epilepsy, Female, Humans, Male, Intellectual Disability, Phenotype, Syndrome, Case-Control Studies, Gene Deletion, CpG Islands, Epigenesis, Genetic

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