Human Gene Module / Chromosome 3 / FEZF2

FEZF2FEZ family zinc finger 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 9
Rare Variants / Common Variants
2 / 2
Aliases
FEZF2, FEZ,  FEZL,  FKSG36,  FLJ10142,  TOF,  ZFP312,  ZNF312
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
3p14.2
Associated Disorders
-
Relevance to Autism

Genetic association has been found between the FEZF2 gene and autism in two large cohorts (AGRE and ACC) of European ancestry and replicated in two other cohorts (CAP and CART) (Wang et al., 2009). In addition, a rare mutation in the FEZF2 gene has been identified in an individual with ASD (Sanders et al., 2012). A de novo loss-of-function variant in FEZF2 was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019; in the same report, a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified FEZF2 as an ASD candidate gene with a q-value 0.1.

Molecular Function

Regulation of transcription

Reports related to FEZF2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Zinc finger protein too few controls the development of monoaminergic neurons. Levkowitz G , et al. (2002) No -
2 Highly Cited Fezl is required for the birth and specification of corticospinal motor neurons. Molyneaux BJ , et al. (2005) No -
3 Recent Recommendation The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Chen B , et al. (2008) No -
4 Recent Recommendation SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons. Kwan KY , et al. (2008) No -
5 Primary Common genetic variants on 5p14.1 associate with autism spectrum disorders. Wang K , et al. (2009) Yes -
6 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
7 Positive Association A genome-wide association study of autism incorporating autism diagnostic interview-revised, autism diagnostic observation schedule, and social res... Connolly JJ , et al. (2012) Yes -
8 Support Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Anazi S , et al. (2016) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1030C>T p.Arg344Cys missense_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.710_721del p.Arg237_Ala240del inframe_deletion Familial Both parents Multiplex 27431290 Anazi S , et al. (2016)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-1476A>G - 2KB_upstream_variant - - - 22935194 Connolly JJ , et al. (2012)
c.-1476A>G C to T 2KB_upstream_variant - - - 19404256 Wang K , et al. (2009)
SFARI Gene score
3

Suggestive Evidence

A single unreplicated association has been reported by Wang et al., 2009 (PMID: 19404256).

Score Delta: Decreased from 4 to 3

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A single unreplicated association has been reported by Wang et al., 2009 (PMID: 19404256).

Reports Added
[New Scoring Scheme]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

A single unreplicated association has been reported by Wang et al., 2009 (PMID: 19404256).

7/1/2014
No data
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4

Increased from No data to 4

Description

A single unreplicated association has been reported by Wang et al., 2009 (PMID: 19404256).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A single unreplicated association has been reported by Wang et al., 2009 (PMID: 19404256).

Krishnan Probability Score

Score 0.57238848515629

Ranking 712/25841 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.
ExAC Score

Score 0.90203350358252

Ranking 3215/18225 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
Sanders TADA Score

Score 0.74810144667959

Ranking 1536/18665 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).
Larsen Cumulative Evidence Score

Score 15.5

Ranking 125/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.23517135705202

Ranking 3685/20870 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.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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