ZFHX4

protein-coding

zinc finger homeobox 4, the group of Zinc fingers C2H2-type|ZF class homeoboxes and pseudogenes

Gene summary

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. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_024721.5

Inheritance

ClinVar variants

P:23U:600B:176

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr8:76,681,239-76,867,281

External References & Databases

Ensembl (ENSG00000091656)

Transcript & Mutation Effects

hg38 • Region Span ~186.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Broad Center for Mendelian Genomics

congenital ptosisNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0008340

Submitter: Illumina

orofacial cleftLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000358

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

syndromic complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*ZFHX4* encodes a transcription factor involved in neural cell maturation and region-specific brain differentiation. *ZFHX4* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2025 (Pérez Baca et al., PMID: 40367947). Affected individuals exhibit variable global developmental delay and intellectual disability, dysmorphic facial features, ophthalmological abnormalities, hypotonia, and behavioral abnormalities including autism (PMID: 40367947). Other less frequent features may include cleft lip and/or palate, short stature, structural brain abnormalities, digit abnormalities, genital abnormalities, and congenital heart defects. Nine variants (6 protein truncating and 3 exon deletions) that have been reported in 9 probands in two publications (PMIDs: 21802062, 40367947) are included in this curation. Most reported variants occur *de novo*. Two of the curated truncating variants were inherited from parents with mild intellectual disability (PMID: 40367947), while an exonic *ZFHX4* deletion was described in a 4-generation family with 5 affected members (PMID: 21802062). Of note, *ZFHX4* loss-of-function variants have been identified in individuals with orofacial cleft, occurring as an apparently isolated finding in some cases (PMIDs: 32574564, 37434517, 39702590). The mechanism of pathogenicity is loss of function. *ZFHX4* haploinsufficiency is considered the major contributor to the clinical manifestations of 8q21.11 microdeletion syndrome (PMIDs: 21802062, 40367947). This gene-disease relationship is also supported by experimental evidence, including mouse and zebrafish models, and protein interactions. In neural progenitor cells, ZFHX4 interacts with proteins encoded by genes associated with neurodevelopmental disorders such as *ZMIZ1*, *WDR81*, *KMT2D*, *ZMYND8*, *NACC1*, and *WASHC4* (PMID: 40367947). In summary, there is strong evidence supporting the relationship between *ZFHX4* and autosomal dominant syndromic complex neurodevelopmental disorder. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 3, 2025 (SOP Version 12).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFHX4 variants in ClinVar

11 Conditions Cataloged

not specifiedTotal: 551

not providedTotal: 226

ZFHX4-related disorderTotal: 76

Ptosis, hereditary congenital, 1Total: 8

Neurodevelopmental disorderTotal: 6

ZFHX4-associated neurodevelopmental disorderTotal: 1

ZFHX4-related syndromeTotal: 1

Congenital corneal opacityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024721.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	100 clinvar	9 clinvar	112
missense			548 clinvar	54 clinvar	13 clinvar	615
nonsense	3 clinvar	4 clinvar	18 clinvar			25
start loss						0
frameshift	6 clinvar	7 clinvar	29 clinvar			42
splice donor/acceptor (+/-2bp)		3 clinvar	2 clinvar			5
Total	9	14	600	154	22	799

Highest pathogenic variant AF is 0.0000065734985

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024721.5	RefSeq	NP_078997.4	10	MANE Select
ENST00000651372.2	Ensembl	ENSP00000498627.1	10	MANE Select
NM_001410934.1	RefSeq	NP_001397863.1	10	Standard
ENST00000517585.1	Ensembl	ENSP00000427775.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mesodermal Commitment Pathway
Ectoderm Differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
zinc ion binding
transcription regulatory region DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000521891
Coding exons: 10
Length: 186068
Individuals with no LoFs: 125464
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125487
p: 0.0000916

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.01	1831	1.96e+3	0.936	0.000108	23823
Missense (PolyPhen)		484	573.79	0.84351		6786
Synonymous	-0.866	812	781	1.04	0.0000494	6987
Loss of Function	9.19	10	118	0.0851	0.00000596	1491

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000063	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in neural and muscle differentiation (By similarity). May be involved in transcriptional regulation. {ECO:0000250}.;

Recessive Scores

pRec: 0.0890

Intolerance Scores

LoFtool: 0.421
RVIS EVS: -1.74
RVIS percentile EVS: 2.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.202

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium