Human Gene Module / Chromosome 16 / ZFHX3

ZFHX3zinc finger homeobox 3

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
10 / 12
Rare Variants / Common Variants
57 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16q22.2-q22.3
Associated Disorders
-
Relevance to Autism

Prez Baca et al., 2024 described 42 individuals with protein-truncating variants or deletions of ZFHX3 exhibiting a syndromic form of intellectual disability characterized by global developmental delay, varying degrees of intellectual disability, behavioral problems (including nine individuals with autism spectrum disorder), hypotonia, recurrent facial features, postnatal growth retardation, and brachydactyly; ZFHX3 haploinsufficiency was found to associate with a specific methylation profile in whole blood extracted DNA. Furthermore, Prez Baca et al., 2024 observed that nuclear abundance of ZFHX3 increased during human brain development and neuronal differentiation and that ZFHX3 interacted with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex and predominantly bound to promoters of genes involved in nervous system development. A number of de novo variants in ZFHX3, including a de novo frameshift variant, have also been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, and the MSSNG cohort, among others (De Rubeis et al., 2014; Iossifov et al., 2014; Hashimoto et al., 2016; Yuen et al., 2017; Lim et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022).

Molecular Function

This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. A heterozygous exonic trinucleotide repeat expansion (GGCn) in this gene has also been associated with spinocerebellar ataxia 4 (SCA4; OMIM 600223) (Wallenius et al., 2024).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZFHX3 (12 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 The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder Hashimoto R , et al. (2015) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
5 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
6 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
7 Support - Wilfert AB et al. (2021) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Trost B et al. (2022) Yes -
11 Support - Joel Wallenius et al. (2024) No -
12 Primary - María Del Rocío Pérez Baca et al. (2024) No ASD, ADD
Rare Variants   (57)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.197C>T p.Ala66Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.679G>A p.Val227Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.900C>T p.His300= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1309G>C p.Gly437Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1504G>A p.Glu502Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2282G>C p.Gly761Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2091G>A p.Pro697= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2578G>A p.Glu860Lys missense_variant De novo - - 36368308 Trost B et al. (2022)
c.1416G>A p.Ala472= synonymous_variant De novo - - 36368308 Trost B et al. (2022)
c.3731C>T p.Thr1244Met missense_variant De novo - - 36368308 Trost B et al. (2022)
- - copy_number_loss De novo - - 38412861 María Del Rocío Pérez Baca et al. (2024)
- - copy_number_loss Unknown - - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.2370C>T p.Cys790= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.5805C>T p.Arg1935= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.7056C>A p.Tyr2352Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.212C>G p.Pro71Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3707A>G p.Asn1236Ser missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.4006G>A p.Ala1336Thr missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.5256T>C p.Val1752= synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.10797C>T p.Pro3599= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.10533T>C p.Gly3511= synonymous_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.3707A>G p.Asn1236Ser missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2532C>A p.His844Gln missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2968C>T p.Arg990Cys missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2685C>T p.Pro895= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.6012C>T p.His2004= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3808C>T p.His1270Tyr missense_variant De novo - Simplex 26582266 Hashimoto R , et al. (2015)
- - copy_number_loss Unknown Not maternal - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.10533_10559del p.Ser3513_Gly3521del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.637C>T p.Gln213Ter stop_gained Unknown - - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.2333_2334insGGCGGC p.Ala783_Ala784dup inframe_insertion De novo - - 35982159 Zhou X et al. (2022)
c.8002C>T p.Arg2668Ter stop_gained Unknown - - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.-5del - frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.4857dup p.His1620ThrfsTer42 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
- - copy_number_loss Familial Paternal Multiplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.1415_1423del p.Ala472_Glu474del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1777G>T p.Glu593Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.2184C>A p.Cys728Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.-23-6923del - frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.3355C>T p.Arg1119Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.3628C>T p.Arg1210Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.3733C>T p.Gln1245Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.4218dup p.Ser1407Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.5749G>T p.Glu1917Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.6004C>T p.Gln2002Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.6604C>T p.Gln2202Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.7660del p.Leu2554Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.6827_6828del p.Ser2276Ter stop_gained De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.5962del p.Tyr1988IlefsTer52 frameshift_variant Unknown - - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.-23-7459_-23-7456del - frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.2876del p.Asp959AlafsTer7 frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.6040C>T p.Gln2014Ter stop_gained Familial - Multi-generational 38412861 María Del Rocío Pérez Baca et al. (2024)
c.1024dup p.Leu342ProfsTer25 frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.2287dup p.Glu763GlyfsTer26 frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.1024dup p.Leu342ProfsTer25 frameshift_variant Unknown Not maternal - 38412861 María Del Rocío Pérez Baca et al. (2024)
c.4510_4511del p.Ser1504ProfsTer5 frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
c.4061_4062del p.Val1354GlufsTer28 frameshift_variant De novo - Simplex 38412861 María Del Rocío Pérez Baca et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
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.

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."

4/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.45269259499781

Ranking 10438/25841 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 0.99999999985926

Ranking 76/18225 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 0.995

Ranking 16/239 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 0.86375207554906

Ranking 4010/18665 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
Zhang D Score

Score -0.009033557391801

Ranking 8962/20870 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
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