Human Gene Module / Chromosome 2 / MBD5

MBD5Methyl-CpG binding domain protein 5

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
19 / 45
Rare Variants / Common Variants
81 / 1
EAGLE Score
46.6
Strong Learn More
Aliases
MBD5, FLJ11113,  FLJ30517,  KIAA1461,  MRD1
Associated Syndromes
2q23.1 microdeletion syndrome, Kleefstra syndrome
Chromosome Band
2q23.1
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
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). 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). Mullegama et al., 2014 demonstrated that 2q23.1 microduplications affecting the MBD5 gene resulted in a duplication syndrome complementary to the 2q23.1 microdeletion syndrome . De novo likely gene-disruptive/protein-truncating variants in the MBD5 gene have been identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (O'Roak et al., 2012; Lim et al., 2017). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified MBD5 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo loss-of-function variant and several missense variants in the MBD5 gene were reported in ASD proband from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified MBD5 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MBD5 (45 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 Autistic behavior
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 disorder 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 developmental delay and obesity Shichiji M , et al. (2013) No Epilepsy, autistic behaviors
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
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 -
27 Support Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes Woodbury-Smith M , et al. (2017) Yes Macrocephaly
28 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
29 Support Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy Han JY , et al. (2017) No ASD, ID
30 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
31 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No Microcephaly
32 Support A novel MBD5 mutation in an intellectually disabled adult female patient with epilepsy: Suggestive of early onset dementia? Verhoeven W , et al. (2019) Yes -
33 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
34 Recent recommendation Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype Frega M , et al. (2020) No -
35 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
36 Support Genetic landscape of autism spectrum disorder in Vietnamese children Tran KT et al. (2020) Yes -
37 Support - Yap CX et al. (2021) Yes -
38 Support - Mullegama SV et al. (2021) No -
39 Support - Qaiser F et al. (2021) No -
40 Support - Chuan Z et al. (2022) No -
41 Support - Zhou X et al. (2022) Yes -
42 Support - Kipkemoi P et al. (2023) No -
43 Support - Martins M et al. (2023) No Stereotypy
44 Support - Shenglan Li et al. (2024) No -
45 Support - Karen Lob et al. () Yes ADHD, DD, epilepsy/seizures
Rare Variants   (81)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss Unknown - - 34622207 Qaiser F et al. (2021)
- - copy_number_gain Unknown - - 23422940 Bonnet C , et al. (2013)
- - translocation De novo - - 22521361 Talkowski ME , et al. (2012)
- - inversion De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - 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 - - 22407754 Motobayashi M , et al. (2012)
- - copy_number_loss Familial Maternal - 33568206 Yap CX et al. (2021)
- - copy_number_loss Unknown - - 17847001 Wagenstaller J , et al. (2007)
- - copy_number_loss De novo - - 22085995 Noh GJ and Graham JM Jr (2011)
- - copy_number_loss De novo - Simplex 23422940 Bonnet C , 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 - Multiplex 23587880 Hodge JC , et al. (2013)
- - copy_number_loss De novo - Simplex 23494922 Shichiji M , et al. (2013)
c.973C>T p.Arg325Ter stop_gained Unknown - - 39136901 Karen Lob et al. ()
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
c.661C>T p.Leu221= stop_gained De novo - - 30763456 Zhou WZ , et al. (2019)
- - copy_number_gain Unknown - Unknown 23632792 Mullegama SV , et al. (2013)
c.550C>T p.Gln184Ter stop_gained De novo - - 35571021 Chuan Z et al. (2022)
c.3685C>T p.Gln1229Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.440C>G p.Ser147Ter stop_gained De novo - - 23422940 Bonnet C , et al. (2013)
c.-286G>A - 5_prime_UTR_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
c.-825A>G - 5_prime_UTR_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
- - copy_number_loss Familial Paternal Simplex 26749308 Turner TN et al. (2016)
c.1963G>A p.Ala655Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3632C>T p.Pro1211Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4972G>A p.Glu1658Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.431C>T p.Thr144Ile missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.688C>T p.Gln230Ter stop_gained De novo - Simplex 28714951 Lim ET , et al. (2017)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
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.2286C>T p.His762= synonymous_variant - - - 17847001 Wagenstaller J , et al. (2007)
- - complex_structural_alteration De novo - Unknown 23587880 Hodge JC , et al. (2013)
- - copy_number_gain Familial Maternal Unknown 23632792 Mullegama SV , et al. (2013)
c.3143C>T p.Thr1048Ile missense_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.3279C>T p.Val1093= synonymous_variant - - - 17847001 Wagenstaller J , et al. (2007)
c.-299_-298del - frameshift_variant De novo - Simplex 32193494 Tran KT et al. (2020)
c.709A>G p.Ile237Val missense_variant Unknown - - 28008202 Ishizuka K , et al. (2016)
- p.Thr157GlnfsTer4 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
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.His912Gln 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)
c.-443G>A - 5_prime_UTR_variant Familial Maternal - 28008202 Ishizuka K , et al. (2016)
c.4170G>A p.Arg1390%3D stop_gained De novo - Simplex 37463579 Kipkemoi P et al. (2023)
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)
- - copy_number_loss Familial Paternal Simplex 28649445 Woodbury-Smith M , et al. (2017)
c.-25_-12del - frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.-23C>A - 5_prime_UTR_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
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)
- - copy_number_loss De novo - Multiplex (monozygotic twins) 23422940 Bonnet C , et al. (2013)
- - copy_number_loss Familial Maternal Extended multiplex 38593811 Shenglan Li et al. (2024)
c.845G>A p.Gly282Asp missense_variant Familial Maternal - 28008202 Ishizuka K , et al. (2016)
c.4337+8C>A - splice_region_variant De novo - Multiplex 31981491 Satterstrom FK et al. (2020)
c.3054+2T>A - splice_site_variant Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.1862A>T p.Asn621Ile missense_variant Familial Paternal - 28008202 Ishizuka K , et al. (2016)
c.2173del p.Ala725ProfsTer20 frameshift_variant Unknown - - 31290275 Verhoeven W , et al. (2019)
c.1918G>T p.Gly640Cys missense_variant Unknown Not paternal - 28008202 Ishizuka K , et al. (2016)
c.2010C>G p.Leu670= synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.2297del p.Thr766IlefsTer18 frameshift_variant Unknown - Simplex 37628781 Martins M et al. (2023)
c.3930A>G p.Gln1310= synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.2009_2012del p.Leu670HisfsTer18 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1327G>A p.Val443Met missense_variant Familial Maternal Simplex 23055267 Cukier HN , et al. (2012)
c.150del p.Thr52HisfsTer31 frameshift_variant De novo - Simplex 22726846 Kleefstra T , et al. (2012)
c.453_454del p.Lys151AsnfsTer3 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.340_347del p.Lys114GlyfsTer35 frameshift_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
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.254_255del p.Arg85AsnfsTer6 frameshift_variant Familial Paternal Multi-generational 28807762 Han JY , et al. (2017)
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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

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."

4/1/2021
1
icon
1

Score remained at 1

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
[Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes2021]
1/1/2021
1
icon
1

Score remained at 1

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
[Analysis of common genetic variation and rare CNVs in the Australian Autism Biobank2021]
4/1/2020
1
icon
1

Score remained at 1

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
[Genetic landscape of autism spectrum disorder in Vietnamese children2020]
1/1/2020
1
icon
1

Score remained at 1

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
[Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype.2020] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
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
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
3S
icon
3S

Decreased from 3S to 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
[A novel MBD5 mutation in an intellectually disabled adult female patient with epilepsy: Suggestive of early onset dementia?2019]
4/1/2019
3S
icon
3S

Decreased from 3S to 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
[Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...2019]
1/1/2019
3S
icon
3S

Decreased from 3S to 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
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
7/1/2017
3S
icon
3S

Decreased from 3S to 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
[Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes.2017] [Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017] [Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy.2017]
4/1/2017
3S
icon
3S

Decreased from 3S to 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
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.2012] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.2013] [Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum diso...2011] [A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with ...2013] [2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features.2011] [Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.2013] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [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] [Extended spectrum of MBD5 mutations in neurodevelopmental disorders.2013] [Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation.2007] [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] [Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.2009] [MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.2014] [Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.2015] [A molecular model for neurodevelopmental disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.2016] [De novo mutations in moderate or severe intellectual disability.2014]
1/1/2017
3S
icon
3S

Decreased from 3S to 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
[Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes.2016]
10/1/2016
3S
icon
3S

Decreased from 3S to 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
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
3S
icon
3S

Decreased from 3S to 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
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.2012] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.2013] [Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum diso...2011] [A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with ...2013] [2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features.2011] [Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.2013] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [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] [Extended spectrum of MBD5 mutations in neurodevelopmental disorders.2013] [Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation.2007] [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] [Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.2009] [MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.2014] [Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.2015] [A molecular model for neurodevelopmental disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA2016]
4/1/2015
3S
icon
3S

Decreased from 3S to 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
[Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.2015] [A molecular model for neurodevelopmental disorders.2015]
10/1/2014
3S
icon
3S

Decreased from 3S to 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
[MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.2014]
7/1/2014
No data
icon
3S

Increased from No data to 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).

4/1/2014
No data
icon
3S

Increased from No data to 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).

Krishnan Probability Score

Score 0.47931065467408

Ranking 8164/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99985233325303

Ranking 740/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.968

Ranking 62/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.094211824712552

Ranking 63/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 50

Ranking 32/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.56568536340851

Ranking 190/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
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
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