Human Gene Module / Chromosome 8 / YWHAZ

YWHAZtyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 16
Rare Variants / Common Variants
16 / 2
Aliases
-
Associated Syndromes
-
Chromosome Band
8q22.3
Associated Disorders
-
Relevance to Autism

YWHAZ was initially proposed as an autism candidate gene based on the discovery of a frameshift variant in this gene in both ASD-affected siblings from a multiplex family (Toma et al., 2014); this variant was subsequently reported in Torrico et al., 2020 to have been inherited from a mother with depression and to result in reduced solubility, a loss in the ability to bind Ser19-phosphorylated tyrosine hydroxylase, and a loss in the ability to form heterodimers with 14-3-3. Additional de novo variants in this gene have been identified in ASD probands, including a rare and potentially deleterious missense variant in a proband from the Autism Sequencing Consortium (Sanders et al., 2015; Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020). Torrico et al., 2020 reported reduced expression of YWHAZ in the cerebellum of ASD cases compared to controls. Popov et al., 2019 reported YWHAZ variants in five individuals presenting with neurodevelopmental phenotypes; one of these individuals presented with autism, while another presented with autistic behavior. YWHAZ has also been proposed as a schizophrenia candidate gene based on genetic association studies, the enrichment of ultra-rare variants in schizophrenia cases, and reduced expression in post-mortem brain tissue from schizophrenia patients (Jia et al., 2004; Middleton et al., 2005; Sun et al., 2011; Fromer et al., 2014; Torrico et al., 2020). Deficiency of YWHAZ in both mice and zebrafish has been shown to result in anatomical and behavioral defects that mirror human phenotypes (Cheah et al., 2015; Xu et al., 2015; Anton-Galindo et al., 2022).

Molecular Function

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. In neurons, this protein regulates spine maturation through the modulation of ARHGEF7 activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
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Reports related to YWHAZ (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association - Jia Y et al. (2004) No -
2 Support - Middleton FA et al. (2005) No -
3 Positive Association - Sun J et al. (2011) No -
4 Support - Cheah PS et al. (2012) No -
5 Primary Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
6 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) No -
7 Support - Xu X et al. (2015) No -
8 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
10 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
11 Support - Popov IK et al. (2019) No ASD or autistic behavior, ID, epilepsy/seizures
12 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
13 Support - Torrico B et al. (2020) Yes -
14 Support - Antón-Galindo E et al. (2022) No -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.40G>T p.Glu14Ter stop_gained De novo - - 31024343 Popov IK et al. (2019)
c.434C>G p.Ser145Ter stop_gained Unknown - - 32545830 Torrico B et al. (2020)
c.-2177C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.379C>T p.Arg127Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.157G>A p.Gly53Arg missense_variant De novo - - 31024343 Popov IK et al. (2019)
c.67G>T p.Ala23Ser missense_variant Unknown - - 32545830 Torrico B et al. (2020)
c.434C>T p.Ser145Leu missense_variant De novo - - 31024343 Popov IK et al. (2019)
c.689C>G p.Ser230Trp missense_variant De novo - - 31024343 Popov IK et al. (2019)
c.294+8247A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.679-43_679-42del - intron_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.294+5626G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.391G>A p.Glu131Lys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.344A>G p.Lys115Arg missense_variant De novo - Simplex 24463507 Fromer M , et al. (2014)
c.687_688dup p.Ser230TyrfsTer44 frameshift_variant De novo - - 31024343 Popov IK et al. (2019)
c.-12+724G>C - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.659dup p.Leu220PhefsTer19 frameshift_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.678+1212A>G - intron_variant - - - 21195589 Sun J et al. (2011)
c.-11-782A>G;c.-12+724A>G - intron_variant - - - 15363479 Jia Y et al. (2004)
SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.60850580841184

Ranking 282/25841 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 0.81717000505601

Ranking 3832/18225 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 0.90583942709671

Ranking 7009/18665 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 0.33068627908634

Ranking 2284/20870 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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