ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23422940 2013 study reporting on three patients with ID with intragenic de novo MBD5 deletions. One patient with ID and an intragenic MBD5 duplication was also reported. Seventy-eight individuals with similar phenotypes had sequencing for MBD5 that identified a de novo nonsense mutation.
21981781 2011 study evaluating 65 individuals with ID, epilepsy, and autism with microdeletions or translocations at 2q23.1. Fourteen alterations focally disrupted MBD5. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression. Copy number alterations of MBD5 were not found in 7878 controls.

Haploinsufficiency phenotype comments:

MBD5 is an epigenetic regulator. Haploinsufficieny of MBD5 results in autosomal dominant mental retardation syndrome type 1. Point mutations within and deletions of MBD5 have been associated with intellectual disability, epilepsy, and autistic features. Haploinsufficiency of the MBD5 gene appears to be responsible for most of the clinical features seen in the 2q23.1 microdeletion syndrome. See also Hodge et al. 2014 (PMID: 23587880) for a discussion of the phenotypic spectrum associated with MBD5 disruptions.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Of note, Chung et al. (2012) (PMID:22085900) describe two patients with "developmental delay, hypotonia, and autistic features associated with duplications of chromosome region 2q23.1-2q23.2." The duplicated regions involved MBD5 and several other genes. The authors report that "a search of the Database of Genomic Variants (DGV) indicated a copy number gain detected in one individual from one study of 776 control samples from individuals in Northern Germany collected as part of the PopGen project." Additional duplications of this region were not seen amongst the rest of the control data set, which included data from over 11,000 other individuals. In 2014, the same group published information on 23 additional individuals with duplications involving 2q23.1 (Mullegama et al.) (PMID: 23632792). Though these duplications varied in size, the MBD5 gene was the only reported gene common to all of these duplications. The authors report that "duplications disrupting any translated or untranslated exons of MBD5 are not present in a control population of 13 991 individuals." Three individuals for whom qRT-PCR were performed demonstrated higher expression levels of MBD5 in lymphocytes relative to controls. Subject SMS376 was the only duplication subject whose CNV did not involve other genes, but the duplication in this subject did not encompass the entire gene. While it is likely that MBD5 is the causative gene in the duplication phenotype, there are currently no reports of individuals with focal MBD5 whole gene duplications. More functional studies are needed to conclusively determine MBD5 triplosensitivity.