Human Gene Module / Chromosome 7 / LRRC4

LRRC4leucine rich repeat containing 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
2 / 0
Aliases
LRRC4, NAG14,  NGL-2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
7q32.1
Associated Disorders
-
Relevance to Autism

Rare de novo variants in the LRRC4 gene (one damaging missense, one loss-of-function) have been identified in ASD probands (Jiang et al., 2013; De Rubeis et al., 2014). Lrrc4 -/- mice were found to display mildly reduced social interaction, suppressed social communication, repetitive behaviors, impaired spatial learning, mild anxiety-like behaviors, suppressed excitatory synapse density and function in the hippocampus, and suppressed excitatory transmission and NMDAR- and mGluR-dependent synaptic plasticity (Um et al., 2018).

Molecular Function

The LRRC4 gene encodes a synaptic adhesion protein that regulates the formation of exitatory synapses through the recruitment of pre-and-postsynaptic proteins and organizes the lamina/pathway-specific differentiation of dendrites.

Reports related to LRRC4 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Jiang YH , et al. (2013) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation. Um SM , et al. (2018) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.238C>G p.Leu80Val missense_variant De novo NA Simplex 23849776 Jiang YH , et al. (2013)
c.10_11del p.Leu4ValfsTer50 frameshift_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Rare de novo variants in the LRRC4 gene (one damaging missense, one loss-of-function) have been identified in ASD probands (Jiang et al., 2013; De Rubeis et al., 2014). Lrrc4 -/- mice were found to display mildly reduced social interaction, suppressed social communication, repetitive behaviors, impaired spatial learning, mild anxiety-like behaviors, suppressed excitatory synapse density and function in the hippocampus, and suppressed excitatory transmission and NMDAR- and mGluR-dependent synaptic plasticity (Um et al., 2018).

Score Delta: Score remained at 4

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

Rare de novo variants in the LRRC4 gene (one damaging missense, one loss-of-function) have been identified in ASD probands (Jiang et al., 2013; De Rubeis et al., 2014). Lrrc4 -/- mice were found to display mildly reduced social interaction, suppressed social communication, repetitive behaviors, impaired spatial learning, mild anxiety-like behaviors, suppressed excitatory synapse density and function in the hippocampus, and suppressed excitatory transmission and NMDAR- and mGluR-dependent synaptic plasticity (Um et al., 2018).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

Rare de novo variants in the LRRC4 gene (one damaging missense, one loss-of-function) have been identified in ASD probands (Jiang et al., 2013; De Rubeis et al., 2014). Lrrc4 -/- mice were found to display mildly reduced social interaction, suppressed social communication, repetitive behaviors, impaired spatial learning, mild anxiety-like behaviors, suppressed excitatory synapse density and function in the hippocampus, and suppressed excitatory transmission and NMDAR- and mGluR-dependent synaptic plasticity (Um et al., 2018).

Krishnan Probability Score

Score 0.53479055030769

Ranking 1495/25841 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 0.87736067160661

Ranking 3405/18225 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
Iossifov Probability Score

Score 0.84

Ranking 203/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.48391839777699

Ranking 415/18665 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).
Zhang D Score

Score 0.36652430693395

Ranking 1827/20870 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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