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MBD5 Haploinsufficiency

Synonyms: 2q23.1 Microdeletion Syndrome, MBD5-Associated Neurodevelopmental Disorders (MAND)

, PhD, , MD, and , PhD.

Author Information

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Estimated reading time: 17 minutes


Clinical characteristics.

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay / intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in about 80%; onset is usually around age two years. Sleep disturbances, present in about 80%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (60%).


Most commonly the diagnosis of MBD5 haploinsufficiency is established in a proband by detection of one of the following alterations on molecular genetic testing:

  • Deletion of 2q23.1 that encompasses all or part of MBD5 (~90% of affected individuals)
  • Intragenic deletion involving one or more exons of MBD5 (~5%)
  • A heterozygous pathogenic sequence variant in MBD5 (~5%)

Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5 is causative.


Treatment of manifestations: A multidisciplinary approach that typically includes specialists in clinical genetics, neurology, child development, behavioral therapy, nutrition/feeding, speech and language therapy, and occupational and physical therapy is recommended. Infants benefit from enrollment in an early-intervention program, and school-age children benefit from an individualized educational program. Speech therapy (including nonverbal methods of communication) should be introduced early. Seizures, behavior problems, and sleep disturbances are treated in a routine manner.

Surveillance: Periodic neurodevelopmental and behavioral evaluations to assist in the management of cognitive and behavioral problems.

Genetic counseling.

MBD5 haploinsufficiency is inherited in an autosomal dominant manner. Typically, deletion of 2q23.1 is de novo; in some instances, an MBD5 pathogenic deletion or MBD5 sequence variant is inherited from a parent who is mildly affected. Rarely, parent-to-child transmission of an unbalanced derivative chromosome involving the 2q23.1 region occurs. Once the genetic alteration resulting in MBD5 haploinsufficiency has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.


Suggestive Findings

MBD5 haploinsufficiency, a neurodevelopmental disorder, should be suspected in individuals with the following findings [Talkowski et al 2011, Hodge et al 2014, Mullegama & Elsea 2016].


  • Intellectual disability (ID), usually moderate to severe
  • Motor delays
  • Severe speech impairment
  • Seizures
  • Sleep disturbance
  • Hypotonia
  • Feeding difficulties, often related to hypotonia


  • Short attention span
  • Autistic-like behaviors that include gaze avoidance, inattention, and repetitive behaviors
  • Self-injury and/or aggressive behaviors

Establishing the Diagnosis

The diagnosis of MBD5 haploinsufficiency is established in a proband with one of the following (see Table 1):

  • Deletion of 2q23.1 that encompasses all or part of MBD5 (~90% of affected individuals)
  • Intragenic deletion involving one or more exons of MBD5 (~5%)
  • A heterozygous pathogenic sequence variant in MBD5 (~5%)
  • Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5

Molecular genetic testing approaches can include a combination of genomic testing (chromosomal microarray analysis [CMA] or more comprehensive genomic testing) and gene-targeted testing (multigene panel or single-gene testing).

Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Because many inherited disorders share the phenotypic findings of ID, seizures, and behavior problems, most children with MBD5 haploinsufficiency are diagnosed by the following recommended testing (CMA and/or a multigene panel) or testing to be considered (comprehensive genomic testing sequencing).

Recommended First-Tier Testing

Chromosomal microarray analysis (CMA) should be the first genetic test as about 90% of MBD5 haploinsufficiency is caused by large, nonrecurrent deletions, which cannot be detected by sequence analysis of MBD5.

Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from MBD5 haploinsufficiency (see Genetically Related Disorders).

Options for Second-Tier Testing

A multigene panel that includes MBD5 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Single-gene testing (sequence analysis of MBD5 followed by gene-targeted deletion/duplication analysis* (if no pathogenic variant is found) may be considered in individuals with features that are highly suggestive of MBD5 haploinsufficiency. However, because many of these features overlap with those of many other genetic disorders with ID, seizures, and behavior issues, a multigene panel or exome sequencing is typically used in lieu of single-gene testing.

*Gene-targeted deletion/duplication analysis should include evaluation of exon 1, which is noncoding, since deletions that include only exon 1 result in MBD5 haploinsufficiency.

Table 1.

Molecular Genetic Testing Used in MBD5 Haploinsufficiency

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
MBD5 CMA 3~90%
Gene-targeted deletion/duplication analysis 4~5%
Sequence analysis 5~5%

See Molecular Genetics for information on allelic variants detected in this gene.


CMA identifies deletion of 2q23.1 (de novo terminal and interstitial deletions).


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Clinical Characteristics

Clinical Description

MBD5 haploinsufficiency is a neurodevelopmental disorder that comprises developmental delay / intellectual disability (ID), severe speech impairment, seizures, sleep disturbances, and behavioral problems with autistic features [Jaillard et al 2009, van Bon et al 2010, Talkowski et al 2011, Noh & Graham 2012].

Developmental delays, evident in all children with MBD5 haploinsufficiency within the first year of life, include delays in gross motor and fine motor development, receptive and expressive language development, and acquisition of social skills. Children typically acquire new skills, without evidence of psychomotor regression.

Motor delays with poor coordination and broad-based/ataxic gait are seen in more than 70% of individuals. The average age of walking is two to three years [van Bon et al 2010, Talkowski et al 2011, Hodge et al 2014].

Language development is severely impaired [van Bon et al 2010]. Most reported children lack speech entirely [Talkowski et al 2011] or have single words or short (2- to 3-word) phrases [Bonnet et al 2013] or (2- to 6-word) sentences [Hodge et al 2014].

Seizures occur in more than 80% of children [Talkowski et al 2011, Hodge et al 2014].

Onset of seizures is usually around age two years [Jaillard et al 2009, van Bon et al 2010, Williams et al 2010, Chung et al 2011, Talkowski et al 2011, Motobayashi et al 2012, Noh & Graham 2012, Bonnet et al 2013, Shichiji et al 2013, Hodge et al 2014].

Although seizure types have not been well characterized, typically only one seizure type is observed in an individual. Seizure types have included absence spells and generalized tonic-clonic, atonic, sleep-related, and startle-induced atonic seizures [Jaillard et al 2009, van Bon et al 2010, Williams et al 2010, Chung et al 2011, Talkowski et al 2011, Motobayashi et al 2012, Noh & Graham 2012, Bonnet et al 2013, Hodge et al 2014].

In the few instances in which EEG studies have been performed, patterns were nonspecific; however, a few individuals were reported to have focal spikes and spike-wave complexes [van Bon et al 2010, Talkowski et al 2011, Hodge et al 2014].

Sleep disturbances, present in about 80% of affected children, include frequent nighttime waking, apparent night terrors in the early part of sleep, and waking in the early hours of the morning [Jaillard et al 2009, van Bon et al 2010, Williams et al 2010, Chung et al 2011, Talkowski et al 2011, Noh & Graham 2012, Bonnet et al 2013, Hodge et al 2014, Mullegama et al 2014].

Many exhibit excessive daytime sleepiness [Mullegama et al 2015b].

Behavior problems (observed in MBD5 haploinsufficiency and other forms of syndromic autism) [Talkowski et al 2011, Hodge et al 2014] include the following:

  • Short attention span and autistic-like behaviors (gaze avoidance, inattention, and repetitive behaviors) [Tan et al 2014] and stereotypic and repetitive behaviors (e.g., teeth grinding, chewing of the hands, and repetitive hand movements) are seen in more than 80% of affected individuals.
  • Self-injury and aggression are seen in more than 60% of individuals.
  • Other behaviors mentioned in approximately 9% of reported individuals include anxiety, hyperactivity, inappropriate happy demeanor, and social withdrawal.

Other findings [Talkowski et al 2011, Hodge et al 2014]

  • Feeding difficulties and constipation, likely related to hypotonia, in more than 90% of infants
  • Mild dysmorphic features (seen in the majority of affected individuals) that may include broad forehead, thick / highly arched eyebrows, outer ear abnormalities (e.g., forward-facing large earlobes, protruding ears, cupped ears), short nose, depressed or wide nasal bridge, downturned corners of the mouth, everted vermilion of the lower lip, tented and thin vermilion of the upper lip
  • Skeletal abnormalities (observed in 65 individuals with MBD5 haploinsufficiency) including: small hands and feet (~75%), fifth finger clinodactyly (~70%), generalized brachydactyly (~41%), short fifth digit of the hands and feet (40%), and sandal gap (~33%) [Talkowski et al 2011]
    Other musculoskeletal abnormalities mentioned in at least two affected individuals each are hip dysplasia, joint laxity, and scoliosis.
  • Cardiovascular abnormalities (seen in ~10%) including atrial septal defect, ventricular septal defect, and pulmonary valve stenosis

Genotype-Phenotype Correlations

Current data show that MBD5 haploinsufficiency is due to decreased MBD5 dosage, which can result from large or small deletions involving MBD5 or pathogenic sequence variants in MBD5. Although no genotype-phenotype correlations distinguish individuals with pathogenic sequence variants from those with deletions, individuals with larger deletions involving multiple genes may exhibit a more severe phenotype.


Clinical features of MBD5 haploinsufficiency are apparent in all individuals with de novo inactivation of one MBD5 allele; however, both phenotypic heterogeneity and variable expressivity are observed.

In some instances, probands have inherited the variant (small MBD5 deletion or duplication or missense variant) from a mildly affected parent in an autosomal dominant manner, suggesting that incomplete penetrance and/or variable expressivity may be associated with this condition [Talkowski et al 2011, Hodge et al 2014].


MBD5 haploinsufficiency was first recognized when overlapping deletions of 2q23.1 were identified in individuals with intellectual disability (ID) and "pseudo-Angelman" phenotypes using array comparative genomic hybridization (array-CGH) [Jaillard et al 2009].

This disorder was initially called 2q23.1 deletion syndrome; however, delineation of the smallest region of overlap among individuals with a 2q23.1 deletion confirmed that haploinsufficiency of MBD5 is responsible for the disorder. In addition, subsequent identification of heterozygous pathogenic sequence variants in MBD5 further supports the use of the term "MBD5 haploinsufficiency."

OMIM uses an outdated term for MBD5 haploinsufficiency: "mental retardation, autosomal dominant 1"; MRD1 (OMIM 156200).


The prevalence of MBD5 haploinsufficiency is not known. Because many individuals with MBD5 haploinsufficiency may go undiagnosed, the prevalence may be greater than observed to date.

Approximately 1% of 4,808 individuals (from 3 cohorts) ascertained for autism spectrum disorder were found to have MBD5 haploinsufficiency when assessed for CNVs involving MBD5 and for MBD5 sequence variants not present in controls [Talkowski et al 2011].

MBD5 haploinsufficiency has been identified worldwide and is present in all ethnic groups.

Differential Diagnosis

The differential diagnosis of MBD5 haploinsufficiency is broad due to the variable spectrum and presence of relatively common abnormal phenotypes that occur in affected individuals (e.g., developmental delay, learning problems, neuropsychiatric disorders). All manifestations of the MBD5 haploinsufficiency can also be seen in individuals with other genomic disorders.

Significant similarity in phenotypic features is observed between MBD5 haploinsufficiency and other neurodevelopmental syndromes. Specific disorders to consider in the differential diagnosis of MBD5 haploinsufficiency include the following:


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MBD5 haploinsufficiency, the following evaluations are recommended:

  • Physical and neurologic examination
  • Developmental assessment including assessment by a physical therapist and/or occupational therapist
  • Speech evaluation including feeding evaluation and nutrition consultation as needed
  • Hearing assessment (as part of the routine evaluation of children with speech delay)
  • EEG if seizures are suspected
  • Cardiac evaluation
  • Sleep history
  • Behavioral assessment
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A multidisciplinary approach to manage the features and specific issues identified is recommended. Specialists in the following fields are often involved: clinical genetics, neurology, child development, behavioral therapy, nutrition/feeding, speech and language therapy, and occupational and physical therapy.



  • Routine management of behavioral issues associated with severe intellectual disability and/or autism spectrum disorder is indicated.
  • Management of sleep disturbance through a combined approach of targeted sleep hygiene (to develop firm daily schedules) and use of daily medications such as melatonin, clonidine, and trazodone may be considered [Mullegama et al 2015b].
  • Routine management is necessary for constipation (which can affect behavior).


Appropriate surveillance includes:

  • Periodic neurodevelopmental and behavioral evaluations to assist in the management of cognitive and behavioral problems;
  • Periodic reevaluations by a clinical geneticist to provide new recommendations and information regarding MBD5 haploinsufficiency.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MBD5 haploinsufficiency is inherited in an autosomal dominant manner. Almost all cases reported to date have resulted from one of the following:

  • A de novo 2q23.1 deletion involving part or all of MBD5 (~90% of probands)
  • An intragenic MBD5 deletion (~5% of probands)
  • An MBD5 pathogenic variant (~5% of probands)
  • Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Each child of an individual with MBD5 haploinsufficiency is at a 50% risk of inheriting the genetic alteration.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a 2q23.1 deletion, MBD5 deletion, or MBD5 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with MBD5 haploinsufficiency.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the genetic alteration resulting in MBD5 haploinsufficiency has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for MBD5 haploinsufficiency and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MBD5 Haploinsufficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
MBD5 2q23​.1 Methyl-CpG-binding domain protein 5 MBD5 database MBD5 MBD5

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MBD5 Haploinsufficiency (View All in OMIM)


Molecular Pathogenesis

Prior to the identification of MBD5 as the gene involved in 2q23.1 deletion syndrome, little was known about MBD5.

Gene structure. The primary MBD5 transcript (NM_018328.4) contains 15 exons. Exons 1-5 are the noncoding exons, followed by ten coding exons. The translation start site is located in exon 6. See Table A, Gene for a detailed summary of gene and protein information.

A second isoform containing eight exons (4 noncoding followed by 4 coding exons) with the same translational start site as the primary transcript has also been reported [Author, personal observation].

De novo deletions involving the noncoding exons have been reported in several cases.

Pathogenic variants. One nonsense and five frameshift pathogenic sequence variants have been reported to date, consistent with haploinsufficiency as a mechanism for MBD5 haploinsufficiency. All pathogenic sequence variants occurred de novo (Table 2).

Table 2.

Selected MBD5 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.150delTp.Thr52HisfsTer31 NM_018328​.4

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. MBD5 has two known isoforms, 1 (UniProtKB ID # Q9P267-1) and 2 (UniProtKB ID # Q9P267-2) [Laget et al 2010].

Isoform 1, the longer primary isoform, has 1,448 amino acids encoded by exons 6-15 [Laget et al 2010]. The protein has two conserved domains, a methyl-binding domain (MBD) and a proline-tryptophan-tryptophan-proline (PWWP) domain, both of which may be found in chromatin-associated proteins.

Isoform 2 is encoded by exons 6-9, with intron 9 being retained, resulting in a protein of 851 amino acids that does not contain the PWWP domain.

Isoforms 1 and 2 have amino acids 1-841 in common. In expression studies Laget et al [2010] showed that while isoform 1 is expressed in all tissues, it is highly expressed in brain and testis, and while isoform 2 is expressed in all tissues, it is highly expressed in brain and ovaries.

MBD5 belongs to MBD family of proteins, which includes MBD1-6 and MeCp2 (encoded by MECP2, the gene involved in Rett syndrome). The MBD proteins play key roles in regulating gene transcription. Most MBD proteins participate in chromatin remodeling and mediate gene silencing through their MBD motifs [Tao et al 2014]. MBD5, in contrast to other MBD proteins, has a deletion of nine amino acids in the first third of the domain and an insertion of six amino acids in the last third of the domain [Laget et al 2010]. Using immunocytochemistry, Camarena et al [2014] showed that MBD5 localizes to non-heterochromatin regions of the nucleus, suggesting that MBD5 acts as a transcriptional activator.

In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids found in numerous proteins involved in cell division, growth, and differentiation.

Abnormal gene product. Haploinsufficiency resulting from deletion or disruption of one MBD5 allele is the cause of MBD5 haploinsufficiency. In extensive expression studies using lymphoblastoid cell lines from persons with various MBD5 deletions, Talkowski et al [2011] showed that MBD5 mRNA expression levels were significantly reduced compared to levels in normal controls.

Haploinsufficiency of MBD5 results in dysregulation of other autism-associated genes, including UBE3A (Angelman syndrome), RAI1 (Smith-Magenis syndrome), TCF4 (Pitt-Hopkins syndrome), MEF2C (5q14.3 deletion syndrome), and FMR1 (FMR1-related disorders) [Mullegama et al 2015a]. Network database analyses utilizing databases such as Gene Mania and SFARI Gene show molecular connections between MBD5 and several autism spectrum disorder-associated genes. The dysregulation of any of these genes can affect pathways and thus alter risks for phenotypes affecting sleep, language, and seizures present in persons with MBD5 haploinsufficiency. Whether MBD5 directly or indirectly regulates some of these genes remains to be determined.


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Chapter Notes

Revision History

  • 27 October 2016 (bp) Review posted live
  • 12 January 2016 (svm) Original submission
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