MBD5 Haploinsufficiency

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 more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

Diagnosis/testing.

The diagnosis of MBD5 haploinsufficiency is established in a proband by identification on molecular genetic testing of a heterozygous deletion of 2q23.1 encompassing all or part of MBD5, or of an intragenic MBD5 pathogenic variant.

Management.

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, sleep disturbances, and constipation are treated in a routine manner. Feeding therapy with gastrostomy tube feeding as needed; treatment of hip dysplasia and scoliosis per orthopedist; treatment of cardiovascular anomalies per cardiologist; family support including social work involvement and care coordination.

Surveillance: Periodic neurodevelopmental and behavioral evaluations to assist in the management of cognitive issues, behavior issues, and sleep disturbance. Assess for seizures, feeding issues, constipation, and family support needs at each visit. Clinical assessment for scoliosis annually.

Genetic counseling.

MBD5 haploinsufficiency is an autosomal dominant disorder typically caused by a de novo genetic alteration. To date, parent-to-child transmission of a 2q23.1 deletion that encompasses all or part of MBD5 has not been reported. Parent-to-child transmissions of MBD5 intragenic deletions and pathogenic sequence variants have been reported. 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].

Neurologic

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

Behavior

• 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 (~80% of affected individuals)
• Intragenic deletion involving one or more exons of MBD5 including noncoding exons 1-5 (~15%)
• A heterozygous pathogenic sequence variant in MBD5 (~5%)
• Rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5

Note: (1) Identification of a heterozygous MBD5 variant of uncertain significance (e.g., intronic deletion that does not affect splicing) does not establish or rule out the diagnosis of MBD5 haploinsufficiency (see Molecular Genetics). (2) MBD5 intragenic deletions limited to noncoding exons 2, 4, and 5 do not result in reduced MBD5 expression and phenotype may be milder than MBD5 haploinsufficiency, although further study is needed [Author, unpublished data].

Molecular genetic testing approaches can include chromosomal microarray analysis, multigene panel, exome sequencing, genome sequencing, 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 (exome or genome sequencing).

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 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: In individuals with features that are highly suggestive of MBD5 haploinsufficiency consider single-gene testing (sequence analysis of MBD5 and gene-targeted deletion/duplication analysis including evaluation of noncoding exon 1). However, because many features of MBD5 haploinsufficiency 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.

Table 1.

Molecular Genetic Testing Used in MBD5 Haploinsufficiency

Clinical Description

MBD5 haploinsufficiency is a neurodevelopmental disorder that comprises developmental delay / intellectual disability (ID), severe speech impairment, seizures, sleep disturbances, and behavior issues with autistic features [Jaillard et al 2009, van Bon et al 2010, Talkowski et al 2011, Noh & Graham 2012]. To date, 105 individuals have been identified with a pathogenic variant in MBD5 [Mullegama & Elsea 2016]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of MBD5 Haploinsufficiency

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 [Bonnet et al 2013, Shichiji et al 2013, Hodge et al 2014, Myers et al 2021].

Although seizure types have not been well characterized, typically only one seizure type is observed in an individual. Seizure types most often include generalized tonic-clonic, focal, atypical absence, tonic, drop attacks, and myoclonic seizures. Atonic, sleep-related, and startle-induced atonic seizures have also been reported [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, Myers et al 2021].

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, Myers et al 2021].

Sleep disturbances, present in about 90% of affected children, include frequent nighttime waking, short sleep duration, 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, Gandhi et al 2021]. Many exhibit excessive daytime sleepiness [Mullegama et al 2015b].

Behavior issues. 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 [Talkowski et al 2011, Hodge et al 2014].

Feeding difficulties and constipation, likely related to hypotonia, are seen in more than 90% of infants.

Skeletal abnormalities (observed in 65 individuals with MBD5 haploinsufficiency) include 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 (reported in ~10%) include atrial septal defect, ventricular septal defect, and pulmonary valve stenosis [Talkowski et al 2011, Hodge et al 2014].

Dysmorphic features are seen in the majority of affected individuals. Microcephaly is common. Additional features 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, and tented and thin vermilion of the upper lip [Talkowski et al 2011, Hodge et al 2014, Mullegama & Elsea 2016].

Genotype-Phenotype Correlations

No genotype-phenotype correlations distinguish individuals with pathogenic sequence variants from those with MBD5 deletions. Individuals with larger deletions involving multiple genes may exhibit a more severe phenotype.

Penetrance

Penetrance is predicted to be complete.

Nomenclature

MBD5 haploinsufficiency was initially referred to as 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."

The commonly used term, "MBD5-associated neurodevelopmental disorder," encompasses MBD5 haploinsufficiency and the neurodevelopmental phenotype associated with nonrecurrent duplications involving MBD5 [Mullegama & Elsea 2016] (see also Genetically Related Disorders). OMIM refers to this disorder as intellectual developmental disorder, autosomal dominant 1 (OMIM 156200). Both MBD5 deletions and duplications are encompassed in the OMIM entry.

Prevalence

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 copy number variants involving MBD5 and for MBD5 sequence variants not present in controls [Talkowski et al 2011].

MBD5 haploinsufficiency has been identified worldwide and in all populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MBD5 haploinsufficiency, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with MBD5 Haploinsufficiency

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.

Table 4.

Treatment of Manifestations in Individuals with MBD5 Haploinsufficiency

Surveillance

Table 5.

Recommended Surveillance for Individuals with 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 ClinicalTrials.gov 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.

Mode of Inheritance

MBD5 haploinsufficiency is an autosomal dominant disorder typically caused by a de novo genetic alteration.

Risk to Family Members

Parents of a proband

• Most probands with MBD5 haploinsufficiency have the disorder as the result of a de novo genetic alteration.
• Rarely, a proband with MBD5 haploinsufficiency has the disorder as the result of a genetic alteration inherited from a parent [Talkowski et al 2011, Hodge et al 2014, Han et al 2017, Myers et al 2021]. (Note: Parent-to-child transmission of a 2q23.1 deletion that encompasses all or part of MBD5 has not been reported to date.)
• For accurate assessment of recurrence risk, evaluation of the parents by molecular genetic or genomic testing that will detect the genetic alteration identified in the proband is recommended. Parental testing for a balanced chromosome rearrangement involving the 2q23.1 region is also recommended.
• If the genetic alteration identified in the proband is not identified in a parent, neither parent has a chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo genetic alteration.
  • The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Parental mosaicism has been reported in several families [Myers et al 2021]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• The family history of some individuals diagnosed with MBD5 haploinsufficiency may appear to be negative because of failure to recognize the disorder in affected family members with a milder phenotype (i.e., variable expressivity) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless genetic testing has demonstrated that neither parent has the genetic alteration identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the genetic alteration identified in the proband, the risk to each sib of inheriting the genetic alteration is 50%. Several families with MBD5 haploinsufficiency recurrence have been reported [Talkowski et al 2011, Hodge et al 2014, Han et al 2017].
• If a parent has a balanced structural chromosome rearrangement involving the 2q23.1 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the causative genetic alteration identified in the proband is not identified in the parents and neither parent has a chromosome rearrangement, the risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [Myers et al 2021].

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an MBD5 haploinsufficiency-related genetic alteration, other members of the parent's family 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the genetic alteration resulting in MBD5 haploinsufficiency has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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]. 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. At the transcriptome level, deletions of MBD5 lead to significant dysregulation of mRNA expression levels of several neurodevelopmental genes such as FOXG1 [Mullegama et al 2021]. MBD5 was shown to be recruited to chromatin by recognition of CG methylation and redundantly represses a subset of genes and transposons without affecting DNA methylation levels [Ichino et al 2021]. 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]. In haploinsufficient RAI1 cells, MBD5 is also dysregulated [Mullegama et al 2015b]. Whether MBD5 directly or indirectly regulates some of these genes remains to be determined.

Mechanism of disease causation. Loss of function

MBD5-specific laboratory technical considerations. Intronic MBD5 deletions that do not affect splicing and deletions and duplications involving the 5’UTR have been reported. Further study is needed to classify many of these variants [Author, personal communication].

Author Notes

The parent Facebook group 2q23.1 Syndromes/MBD5 Disorders/MAND Caregiver Support Network is a support group for families with children who have a molecular diagnosis of MBD5-associated neurodevelopmental disorder (MAND).

Sureni V Mullegama, PhD, FACMG, is a board-certified clinical molecular geneticist. Her clinical and scholarly work is rooted in providing answers to patients and their families regarding the genetic conditions they have. The answers may come through clinical genetic testing, molecular genetic research, or genetics education. Her interests include autism spectrum disorders, cohesinopathies, epigenetic disorders, epilepsy disorders and other neurogenetic conditions. She studies the following disorders: Smith-Magenis syndrome, MAND – 2q23.1 deletion syndrome and 2q23.1 duplication syndrome, and Mullegama-Klein-Martinez syndrome.
SHSU College of Osteopathic Medicine website

Roberto Mendoza-Londono, MD, MSc, FACMG, is a licensed clinical geneticist. His interests include genetics of skeletal dysplasias and connective tissue disorders. His research interests include the identification of the genetic basis and molecular pathophysiologic mechanisms underlying common and novel genetic disorders, and the delineation of the natural history and best management strategies for patients with connective tissue disorders.
LinkedIn page

Sarah H Elsea, PhD, FACMG, is a board-certified clinical biochemical geneticist. Her research is targeted toward defining the biochemical mechanisms and molecular pathways affected in human genetic disease. Investigations of neurodevelopmental disorders complicated by obesity and circadian rhythm defects, including autism, intellectual disability, seizures, and behavioral phenotypes, are a primary focus. Studies include the clinical and molecular analysis of genomic conditions, wherein deletion or duplication of a portion of the genome is the primary underlying etiology, leading to altered gene dosage. Disorders include MAND – 2q23.1 deletion syndrome and 2q23.1 duplication syndrome, as well as 2q37.3 deletion syndrome, Smith-Magenis syndrome, Potocki-Lupski syndrome, Pitt-Hopkins syndrome, and others.
Web page

Acknowledgments

The authors would like to thank the individuals with MAND and their families for their continued interest and support of MAND research. The parents with children of MAND are the true experts on this disorder; without their help this review and the ongoing research to better define and understand MAND would not be possible.

Revision History

• 28 April 2022 (sw) Comprehensive update posted live
• 27 October 2016 (bp) Review posted live
• 12 January 2016 (svm) Original submission

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