Human Gene Module / Chromosome 2 / PER2

PER2period circadian clock 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 8
Rare Variants / Common Variants
14 / 0
EAGLE Score
6.75
Moderate Learn More
Aliases
PER2, FASPS,  FASPS1
Associated Syndromes
-
Chromosome Band
2q37.3
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Molecular Function

This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PER2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients Yang Z , et al. (2015) Yes -
3 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Hoang N et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Chan AJS et al. (2022) Yes -
8 Support - Tuncay IO et al. (2023) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1308-4G>A - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.2414G>A p.Arg805Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1911G>A p.Pro637%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3682C>G p.Pro1228Ala missense_variant Unknown - - 25957987 Yang Z , et al. (2015)
c.192G>T p.Glu64Asp missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3088C>T p.Gln1030Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
ACTCT>ACT p.Ile385fs frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.178G>A p.Asp60Asn missense_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.2365A>T p.Lys789Ter stop_gained Familial Paternal Simplex 28263302 C Yuen RK et al. (2017)
- p.Pro1246fs frameshift_variant Unknown Not maternal Simplex 28263302 C Yuen RK et al. (2017)
c.3330_3331del p.Asn1111Ter frameshift_variant Familial Maternal - 36309498 Chan AJS et al. (2022)
c.1931del p.Arg644ProfsTer4 frameshift_variant Familial Maternal Simplex 33474825 Hoang N et al. (2021)
ENST00000254657.8:2191G>A p.Ala731Thr missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.596del p.Leu199ArgfsTer93 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

1/1/2021
2
icon
2

Score remained at 2

Description

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Reports Added
[Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.2015] [Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene2021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2017
icon
3

Increased from to 3

Description

A de novo loss-of-function variant in the PER2 gene was observed in an ASD proabnd from the Simons Simplex Collection in Iossifov et al., 2014. Yuen et al., 2017 identified additional PER2 variants by whole genome sequencing in four ASD families, including a de novo LoF variant in a simplex family from the ASD: Genomes to Outcome Study cohort. Despite being a mutation-intolerant gene with a pLI score of 0.93, PER2 did not meet the statistical significance criteria used in Yuen et al., 2017 to be designated as an ASD candidate gene, which was a higher-than-expected mutation rate (false discovery rate < 15%).

Krishnan Probability Score

Score 0.49125692507822

Ranking 5689/25841 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 0.93300468704054

Ranking 2894/18225 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 0.67558475193606

Ranking 1017/18665 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 0.50296439979804

Ranking 505/20870 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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