Human Gene Module / Chromosome 2 / MBD5

MBD5Methyl-CpG binding domain protein 5

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
10 / 27
Rare Variants / Common Variants
105 / 1
Aliases
MBD5, FLJ11113,  FLJ30517,  KIAA1461,  MRD1
Associated Syndromes
2q23.1 microdeletion syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q23.1
Associated Disorders
DD/NDD, EP, EPS, ID, ASD
Relevance to Autism

MBD5 was originally identified as a candidate gene in a report describing copy number variation in patients with unexplained mental retardation (Wagenstaller et al., 2007). Since that report, numerous studies have implicated MBD5 haploinsufficiency as being associated with intellectual disability, epilepsy, and autism spectrum disorder (Jaillard et al., 2009; van Bon et al., 2010; Williams et al., 2010; Talkowski et al., 2011). More recently, a balanced chromosomal abnormality (BCA) leading to MBD5 disruption was identified in an ASD case (Talkowski et al., 2012).

Molecular Function

This gene encodes a member of the methyl-CpG-binding domain (MBD) family. Mutations in this gene cause mental retardation autosomal dominant type 1. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.

Reports related to MBD5 (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Wagenstaller J , et al. (2007) No -
2 Support 2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features? Jaillard S , et al. (2008) No -
3 Support The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. van Bon BW , et al. (2009) No -
4 Highly cited Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Williams SR , et al. (2009) No -
5 Support Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum diso... Talkowski ME , et al. (2011) No DD, epilepsy
6 Support 2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features. Noh GJ and Graham JM Jr (2011) No -
7 Support Neurodevelopmental features in 2q23.1 microdeletion syndrome: report of a new patient with intractable seizures and review of literature. Motobayashi M , et al. (2012) No Epilepsy
8 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
9 Support Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Talkowski ME , et al. (2012) Yes -
10 Support Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Kleefstra T , et al. (2012) No -
11 Support The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1. Cukier HN , et al. (2012) Yes -
12 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
13 Support Extended spectrum of MBD5 mutations in neurodevelopmental disorders. Bonnet C , et al. (2013) No -
14 Support A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with ... Shichiji M , et al. (2013) No Epilepsy
15 Recent recommendation Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Hodge JC , et al. (2013) No ASD
16 Recent Recommendation Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Mullegama SV , et al. (2013) Yes DD, ID
17 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
18 Recent recommendation MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes. Mullegama SV , et al. (2014) No Sleep disturbance
19 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Absent speech
20 Recent Recommendation Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder. Mullegama SV , et al. (2015) No -
21 Recent recommendation A molecular model for neurodevelopmental disorders. Gigek CO , et al. (2015) No -
22 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
23 Recent recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Turner TN , et al. (2016) Yes -
24 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No PDD (1 case)
25 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) Yes -
26 Support Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes. Ishizuka K , et al. (2016) Yes -
Rare Variants   (105)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 17847001 Wagenstaller J , et al. (2007)
c.431C>T p.Thr144Ile missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.1382G>A p.Arg461His missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.1962C>A p.Asp654Glu missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.1963G>A p.Ala655Thr missense_variant Familial - - 17847001 Wagenstaller J , et al. (2007)
c.2569G>A p.Ala857Thr missense_variant Familial - - 17847001 Wagenstaller J , et al. (2007)
c.3143C>T p.Thr1048Ile missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.2286C>T p.(=) synonymous_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.3279C>T p.(=) synonymous_variant - - - 17847001 Wagenstaller J , et al. (2007)
- - copy_number_loss De novo - - 18812405 Jaillard S , et al. (2008)
- - copy_number_loss De novo - - 19809484 van Bon BW , et al. (2009)
- - copy_number_loss De novo - - 19809484 van Bon BW , et al. (2009)
- - copy_number_loss De novo - - 22085995 Noh GJ and Graham JM Jr (2011)
- - copy_number_loss De novo - - 22407754 Motobayashi M , et al. (2012)
c.453_454del p.Lys151fs frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
- - translocation De novo - - 22521361 Talkowski ME , et al. (2012)
c.150delT p.Thr52HisfsTer31 frameshift_variant De novo - Simplex 22726846 Kleefstra T , et al. (2012)
c.1327G>A p.Val443Met missense_variant Familial Maternal Simplex 23055267 Cukier HN , et al. (2012)
c.3740T>C p.Ile1247Thr missense_variant Familial Paternal Multiplex 23055267 Cukier HN , et al. (2012)
c.3806A>G p.Tyr1269Cys missense_variant Familial Paternal Multiplex 23055267 Cukier HN , et al. (2012)
c.3896G>A p.Arg1299Gln missense_variant Familial Maternal Multiplex 23055267 Cukier HN , et al. (2012)
c.114-53T>C - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.398-22C>A - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.2010C>G p.(=) synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.-23C>A - 5_prime_UTR_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.3930A>G p.(=) synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.3054+2T>A - splice_site_variant Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss De novo - Multiplex (monozygotic twins) 23422940 Bonnet C , et al. (2013)
- - copy_number_gain Unknown - - 23422940 Bonnet C , et al. (2013)
- - copy_number_loss De novo - Simplex 23422940 Bonnet C , et al. (2013)
c.440C>G p.Ser147Ter stop_gained De novo - - 23422940 Bonnet C , et al. (2013)
- - copy_number_loss De novo - Likely simplex 23494922 Shichiji M , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown Likely inherited Multiplex 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss Unknown - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - complex_structural_alteration De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_gain Familial Maternal Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Familial Maternal Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Familial Maternal Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
- p.Thr157GlnfsTer4 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.340_347del p.Lys114GlyfsTer35 frameshift_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
- - copy_number_loss Familial Paternal Simplex 26749308 Turner TN , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.288_301del p.Lys98Ter frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.-825A>G - 5_prime_UTR_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.-443G>A - 5_prime_UTR_variant Familial Maternal - 28008202 Ishizuka K , et al. (2016)
c.-286G>A - 5_prime_UTR_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.709A>G p.Ile237Val missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.845G>A p.Gly282Asp missense_variant Familial Maternal - 28008202 Ishizuka K , et al. (2016)
c.1862A>T p.Asn621Ile missense_variant Familial Paternal - 28008202 Ishizuka K , et al. (2016)
c.1918G>T p.Gly640Cys missense_variant Unknown Not paternal - 28008202 Ishizuka K , et al. (2016)
c.2025G>C p.Met675Ile missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.2173G>T p.Ala725Ser missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.2550A>G p.Ile850Met missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.2725C>T p.His909Tyr missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.2736C>A p.His912Glu missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.2926T>A p.Phe976Ile missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.3442A>G p.Asn1148Asp missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.4045G>A p.Val1349Met missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.4070G>A p.Ser1357Asn missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.236G>A p.Gly79Glu missense_variant - - - 21981781 Talkowski ME , et al. (2011)
SFARI Gene score
3S

Suggestive Evidence, Syndromic

MBD5 was originally identified as a candidate gene in a report describing copy number variation in patients with unexplained mental retardation (Wagenstaller et al., 2007). Since that report, numerous studies have implicated MBD5 haploinsufficiency as being associated with intellectual disability, epilepsy, and autism spectrum disorder (Jaillard et al., 2009; van Bon et al., 2010; Williams et al., 2010; Talkowski et al., 2011). In particular, Talkowski et al. (2011) showed that the MBD5 locus defines the critical region of 2q23.1 microdeletion syndrome and showed significant reduction in MBD5 RNA expression in lymphoblastoid cell lines of individuals with MBD5 deletions. That report also showed association of a missense variant (Gly79Glu) in 6/747 ASD cases compared to 3/3042 controls (P=0.012). More recently, a balanced chromosomal abnormality (BCA) leading to MBD5 disruption was identified in an ASD case (Talkowski et al., 2012).

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

04-01-2017
3S

Initial score established: 3S

Description

MBD5 was originally identified as a candidate gene in a report describing copy number variation in patients with unexplained mental retardation (Wagenstaller et al., 2007). Since that report, numerous studies have implicated MBD5 haploinsufficiency as being associated with intellectual disability, epilepsy, and autism spectrum disorder (Jaillard et al., 2009; van Bon et al., 2010; Williams et al., 2010; Talkowski et al., 2011). In particular, Talkowski et al. (2011) showed that the MBD5 locus defines the critical region of 2q23.1 microdeletion syndrome and showed significant reduction in MBD5 RNA expression in lymphoblastoid cell lines of individuals with MBD5 deletions. That report also showed association of a missense variant (Gly79Glu) in 6/747 ASD cases compared to 3/3042 controls (P=0.012). More recently, a balanced chromosomal abnormality (BCA) leading to MBD5 disruption was identified in an ASD case (Talkowski et al., 2012).

Reports Added
[Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.2013] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.2013] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.2009] [Extended spectrum of MBD5 mutations in neurodevelopmental disorders.2013] [De novo mutations in moderate or severe intellectual disability.2014] [Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation.2007] [The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.2012] [MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.2014] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.2009] [2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?2008] [Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum diso...2011] [Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.2016] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with ...2013] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [A molecular model for neurodevelopmental disorders.2015] [2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features.2011] [Neurodevelopmental features in 2q23.1 microdeletion syndrome: report of a new patient with intractable seizures and review of literature.2012] [Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability.2012] [Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.2015]
CNVs associated with MBD5(1 CNVs)
2q23.1 14 Deletion-Duplication 20  /  75
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
HDGFRP2 Hepatoma-derived growth factor-related protein 2 Human Protein Binding 84717 Q7Z4V5-2
KDM1B Lysine-specific histone demethylase 1B Human Protein Binding 221656 Q8NB78
NME2P1 Putative nucleoside diphosphate kinase Human Protein Binding O60361
PMVK Phosphomevalonate kinase Human Protein Binding 10654 Q15126
Submit New Gene

Report an Error