Human Gene Module / Chromosome 1 / ZBTB18

ZBTB18zinc finger and BTB domain containing 18

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
6 / 14
Rare Variants / Common Variants
33 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q44
Associated Disorders
-
Relevance to Autism

Multiple de novo variants in the ZBTB18 gene, including two de novo loss-of-function (LoF) variants, have been reported in ASD probands (De Rubeis et al., 2014; Feliciano et al., 2019; Wang et al., 2020; Zhou et al., 2022; Trost et al., 2022; More et al., 2023). A case-control mutation burden analysis of 16,000 cases with neurodevelopmental disorders and nonpsychiatric controls from ExAC in Wang et al., 2020 identified ZBTB18 as a gene showing a significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%). Heterozygous mutations in the ZBTB18 gene are responsible for autosomal dominant intellectual developmental disorder-22 (MRD22; OMIM 612337), a disorder characterized by impaired intellectual development with frequent cooccurrence of corpus callosum anomalies, hypotonia, microcephaly, growth problems, and variable facial dysmorphism; stereotypies have been reported in a subset of affected individuals (Lopes et al., 2016; Cohen et al., 2017; Depienne et al., 2017; Trinh et al., 2019).

Molecular Function

This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZBTB18 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Identification of novel genetic causes of Rett syndrome-like phenotypes Lopes F , et al. (2016) No Stereotypy
3 Support - Cohen JS et al. (2017) No ADHD, ID, epilepsy/seizures, stereotypy
4 Support - Depienne C et al. (2017) No Epilepsy/seizures, stereotypy
5 Support - Trinh J et al. (2019) No Stereotypy
6 Primary Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) No ASD
8 Support - Zhou X et al. (2022) Yes -
9 Support - Trost B et al. (2022) Yes -
10 Support - More RP et al. (2023) Yes -
11 Support - Spataro N et al. (2023) No Autistic features, stereotypy
12 Support - Kipkemoi P et al. (2023) Yes -
13 Support - Alejandro J Brea-Fernández et al. (2023) No Epilepsy/seizures
14 Support - Axel Schmidt et al. (2024) No ID
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.697C>T p.Gln233Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1183C>T p.Gln395Ter stop_gained De novo - - 27598823 Cohen JS et al. (2017)
c.1414G>A p.Glu472Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1444C>T p.Arg482Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1483C>T p.Arg495Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.583C>T p.Arg195Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.1517C>T p.Ser506Leu missense_variant De novo - - 36368308 Trost B et al. (2022)
c.44A>G p.His15Arg missense_variant De novo - - 28283832 Depienne C et al. (2017)
c.133C>T p.Arg45Ter stop_gained De novo - Simplex 27598823 Cohen JS et al. (2017)
c.556C>T p.Arg186Ter stop_gained De novo - Simplex 26740508 Lopes F , et al. (2016)
c.1301T>C p.Leu434Pro missense_variant De novo - - 28283832 Depienne C et al. (2017)
c.1391G>A p.Arg464His missense_variant De novo - - 28283832 Depienne C et al. (2017)
c.599del p.Ser200Ter frameshift_variant De novo - - 28283832 Depienne C et al. (2017)
c.1361A>T p.Lys454Met missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.246dup p.Ala83ArgfsTer7 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1283T>G p.Phe428Cys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1425C>T p.His475= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.448del p.Val150SerfsTer11 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.570del p.Asn191ThrfsTer31 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.658dup p.Thr220AsnfsTer27 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1307G>A p.Arg436His missense_variant De novo - Simplex 31238879 Trinh J et al. (2019)
c.334G>C p.Val112Leu missense_variant De novo - Multiplex 36702863 More RP et al. (2023)
c.1382A>G p.Asn461Ser missense_variant De novo - Simplex 27598823 Cohen JS et al. (2017)
c.1390C>T p.Arg464Cys missense_variant De novo - Simplex 27598823 Cohen JS et al. (2017)
c.686_687del p.Glu229ValfsTer17 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.916_917del p.Arg306GlyfsTer4 frameshift_variant De novo - - 27598823 Cohen JS et al. (2017)
c.1279_1307dup p.His437LeufsTer36 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1306C>T p.Arg436Cys missense_variant Unknown Not maternal - 36980980 Spataro N et al. (2023)
c.1147del p.Leu383CysfsTer16 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.626_627insTCTC p.Glu209AspfsTer39 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1444C>T p.Arg482Cys missense_variant De novo - - 38056433 Alejandro J Brea-Fernández et al. (2023)
c.204_205del p.Asp70HisfsTer19 frameshift_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.141C>G p.His47Gln missense_variant De novo - Multiplex (monozygotic twins) 38056433 Alejandro J Brea-Fernández et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

Krishnan Probability Score

Score 0.60986565736328

Ranking 243/25841 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 0.97012354907433

Ranking 2356/18225 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
Sanders TADA Score

Score 0.933362183727

Ranking 12247/18665 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
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