Human Gene Module / Chromosome X / ZFX

ZFXzinc finger protein X-linked

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp22.11
Associated Disorders
-
Relevance to Autism

Shepherdson et al., 2024 described a cohort of 18 individuals with germline variants in the ZFX gene who presented with an X-linked neurodevelopmental disorder characterized by developmental delay/intellectual disability, behavioral abnormalities (including a diagnosis of autism spectrum disorder in six individuals), hypotonia, congenital anomalies, and recurrent facial features including thickening and medial broadening of the eyebrows, variations in facial shape, external eye abnormalities, long and/or smooth philtrum, and ear abnormalities. Additional functional assessment in Shepherdson et al., 2024 demonstrated that disease-associated ZFX missense variants resulted in altered target gene expression, while behavioral characterization of zfx knockout zebrafish demonstrated neurocognitive abnormalities. Additional coding variants in the ZFX gene have been previously identified in ASD probands (Chahrour et al., 2012; Ruzzo et al., 2019; Zhou et al., 2022).

Molecular Function

This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZFX (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism Chahrour MH , et al. (2012) Yes -
2 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Primary - James L Shepherdson et al. (2024) No ASD or autistic features, ADHD
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1863G>A p.Gln621= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.-29+2924A>G - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2290C>T p.Arg764Trp missense_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.2312C>T p.Thr771Met missense_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.2321A>G p.Tyr774Cys missense_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.2357G>A p.Arg786Gln missense_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.2357G>A p.Arg786Gln missense_variant Familial Maternal - 38325380 James L Shepherdson et al. (2024)
c.768dup p.Lys257Ter stop_gained Familial Maternal Simplex 38325380 James L Shepherdson et al. (2024)
c.423_424del p.Ser142Ter stop_gained Familial Maternal Simplex 38325380 James L Shepherdson et al. (2024)
G>C p.Glu83Gln missense_variant Unknown - Multiplex (monozygotic twins) 22511880 Chahrour MH , et al. (2012)
c.529dup p.Ser177PhefsTer12 frameshift_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.2290C>T p.Arg764Trp missense_variant Familial Maternal Simplex 38325380 James L Shepherdson et al. (2024)
c.1319dup p.Leu440PhefsTer21 frameshift_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.1996_1997del p.Met666ValfsTer2 frameshift_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.1205_1206dup p.Arg403GlufsTer12 frameshift_variant De novo - Simplex 38325380 James L Shepherdson et al. (2024)
c.115_116del p.Val39PhefsTer14 frameshift_variant Familial Maternal Simplex 38325380 James L Shepherdson et al. (2024)
c.2321A>G p.Tyr774Cys missense_variant Familial Maternal Extended multiplex 38325380 James L Shepherdson 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 0.49598304598199

Ranking 2722/25841 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 0.98613344982167

Ranking 1950/18225 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 0.93800054305279

Ranking 13714/18665 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 0.37368638608286

Ranking 1746/20870 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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