Human Gene Module / Chromosome 8 / ZFHX4

ZFHX4zinc finger homeobox 4

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
46 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
8q21.13
Associated Disorders
-
Relevance to Autism

Perez Baca et al., 2025 reported 63 individuals (57 probands and 6 affected family members) with protein-truncating variants (n=41), copy number variants (n=21), or an inversion (n=1) affecting the ZFHX4 gene presenting with a variable neurodevelopmental syndrome characterized by developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral abnormalities (of which stereotypies (n=7) and autism (n=10) were the most frequently reported), short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis; while ZFHX4 deletions showed a mild methylation profile, protein-truncating variants did not. Moreover, the authors of this study implicated ZFHX4 interactors in transcriptional regulation and development and its target gene in neural development using multi-omics data and also observed that zebrafish zfhx4 crispants displayed craniofacial/medulla oblongata defects and reduced movement frequency. Additional de novo variants in ZFHX4, including two de novo loss-of-function variants and several de novo missense variants, have been identified in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022).

Molecular Function

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to ZFHX4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Support - Trost B et al. (2022) Yes -
4 Primary - María Del Rocío Pérez Baca et al. (2025) No ASD, ADHD, stereotypy
5 Support - Himanshu Goel et al. (2025) Yes -
Rare Variants   (46)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.22C>A p.Pro8Thr missense_variant De novo - - 36368308 Trost B et al. (2022)
- - inversion De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1096G>A p.Ala366Thr missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2699C>T p.Ala900Val missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
- - copy_number_loss De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
- - copy_number_loss Unknown - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.8796del p.Arg2933GlufsTer4 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
- - copy_number_loss Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
- - copy_number_loss Familial Paternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.250G>T p.Glu84Ter stop_gained Unknown - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.2300G>A p.Trp767Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5389C>T p.Gln1797Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5656A>T p.Lys1886Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5695C>T p.Arg1899Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.7990C>T p.Gln2664Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.3093+1G>T p.? splice_site_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.3965-1G>A p.? splice_site_variant Unknown - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5013_5014insGCC p.Asn1671_Lys1672insAla inframe_insertion De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5010_5011delinsTAG p.Leu1670PhefsTer3 frameshift_variant De novo - Multiplex 36368308 Trost B et al. (2022)
c.2041C>T p.Gln681Ter stop_gained Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1965_1972delinsG p.Tyr655Ter stop_gained De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.6528G>A p.Trp2176Ter stop_gained Familial Paternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.954del p.Ser319ProfsTer3 frameshift_variant Unknown - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1223del p.Leu408ArgfsTer7 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1230dup p.Leu411AlafsTer3 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.2707del p.Leu903TyrfsTer18 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.2883del p.Cys962AlafsTer27 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.4326dup p.His1443ThrfsTer8 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.3341del p.Gly1114GlufsTer14 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.4150del p.Arg1384GlyfsTer57 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.990_1000del p.Pro331LeufsTer36 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1889_1896del p.Gly630AspfsTer16 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5507_5508del p.Gln1836ArgfsTer4 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5134_5135del p.Gln1712ValfsTer64 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5214_5215del p.Phe1739SerfsTer37 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5656_5657del p.Lys1886GlufsTer33 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.6772_6775del p.Gln2258SerfsTer69 frameshift_variant De novo - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.7644_7648del p.Gly2549ThrfsTer35 frameshift_variant Unknown - - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.1020dup p.Ser341IlefsTer30 frameshift_variant Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.7045del p.Thr2349GlnfsTer43 frameshift_variant Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.6564_6567del p.Asn2188LysfsTer12 frameshift_variant Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.7644_7648del p.Gly2549ThrfsTer35 frameshift_variant Familial Paternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.8619_8622del p.His2874SerfsTer30 frameshift_variant Familial Paternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.5850_5851delAT p.Cys1951TrpfsTer2 frameshift_variant Familial Maternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
c.3233_3239delinsCAGTCTCC p.Arg1078ProfsTer19 frameshift_variant Familial Paternal - 40367947 María Del Rocío Pérez Baca et al. (2025)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

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."

7/1/2025
3S

Initial score established: 3S

Krishnan Probability Score

Score 0.58887746721683

Ranking 491/25841 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 0.99999964229011

Ranking 245/18225 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 0.94923232309808

Ranking 18007/18665 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 0.15434492999562

Ranking 5094/20870 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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