Human Gene Module / Chromosome 5 / HOMER1

HOMER1Homer homolog 1 (Drosophila)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
8 / 0
Aliases
HOMER1, HOMER,  HOMER1A,  HOMER1B,  HOMER1C,  SYN47,  Ves-1
Associated Syndromes
Phelan-McDermid syndrome
Chromosome Band
5q14.1
Associated Disorders
-
Relevance to Autism

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012).

Molecular Function

This gene encodes a member of the homer family of dendritic proteins. Members of this family regulate group 1 metabotrophic glutamate receptor function.

SFARI Genomic Platforms
Reports related to HOMER1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome Ronesi JA , et al. (2012) No -
2 Primary High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism Kelleher RJ 3rd , et al. (2012) Yes -
3 Recent Recommendation Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex Fatemi SH , et al. (2013) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Recent Recommendation Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment Banerjee A , et al. (2016) No -
6 Support - Lin R et al. (2021) No -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.162+19G>T - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.528-11T>G - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.968G>A p.Arg323His missense_variant De novo - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.*197C>T - 3_prime_UTR_variant Familial Paternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.195G>T p.Met65Ile missense_variant Familial Maternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.290C>T p.Ser97Leu missense_variant Familial Maternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.425C>T p.Pro142Leu missense_variant Familial Paternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.634A>G p.Lys212Glu missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012). PMID 22267161 demonstrated that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in a fragile X syndrome mouse model. Significant decreases in HOMER1 protein levels were observed in the BA9 and vermis of adult subjects with autism compared to controls in PMID 23803181. Virally-mediated overexpression of Homer1 in the basal and lateral nucleus of the amygdala impaired auditory fear conditioning and reduced social interaction in rats, while having no influence on open-field behavior (Banerjee et al., 2016).

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012). PMID 22267161 demonstrated that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in a fragile X syndrome mouse model. Significant decreases in HOMER1 protein levels were observed in the BA9 and vermis of adult subjects with autism compared to controls in PMID 23803181. Virally-mediated overexpression of Homer1 in the basal and lateral nucleus of the amygdala impaired auditory fear conditioning and reduced social interaction in rats, while having no influence on open-field behavior (Banerjee et al., 2016).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012). PMID 22267161 demonstrated that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in a fragile X syndrome mouse model. Significant decreases in HOMER1 protein levels were observed in the BA9 and vermis of adult subjects with autism compared to controls in PMID 23803181. Virally-mediated overexpression of Homer1 in the basal and lateral nucleus of the amygdala impaired auditory fear conditioning and reduced social interaction in rats, while having no influence on open-field behavior (Banerjee et al., 2016).

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

Increased from to 4

Description

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012). PMID 22267161 demonstrated that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in a fragile X syndrome mouse model. Significant decreases in HOMER1 protein levels were observed in the BA9 and vermis of adult subjects with autism compared to controls in PMID 23803181. Virally-mediated overexpression of Homer1 in the basal and lateral nucleus of the amygdala impaired auditory fear conditioning and reduced social interaction in rats, while having no influence on open-field behavior (Banerjee et al., 2016).

Krishnan Probability Score

Score 0.49045596977077

Ranking 6115/25841 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 0.99592202439131

Ranking 1453/18225 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 0.93595566047827

Ranking 13041/18665 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 29

Ranking 74/461 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 0.43350097467116

Ranking 1085/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ABI3 ABI family, member 3 Human Protein Binding 51225 Q9P2A4
C19ORF57 chromosome 19 open reading frame 57 Human Protein Binding 79173 Q0VDD7
C1orf116 chromosome 1 open reading frame 116 Human Protein Binding 79098 Q9BW04
C22ORF41 synaptonemal complex central element protein 3 Human Protein Binding 644186 A1L190
KIF2B Kinesin-like protein KIF2B Human Protein Binding 84643 Q8N4N8
Klk1 kallikrein 1 Mouse Protein Binding 16612 P15947
TRPC2 transient receptor potential cation channel, subfamily C, member 2, pseudogene Human Protein Binding 7221 N/A
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