Human Gene Module / Chromosome 6 / LRFN2

LRFN2leucine rich repeat and fibronectin type III domain containing 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
18 / 1
Aliases
LRFN2, FIGLER2,  KIAA1246,  SALM1
Associated Syndromes
-
Chromosome Band
6p21.2-p21.1
Associated Disorders
-
Relevance to Autism

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

Molecular Function

The protein encoded by the LRFN2 gene promotes neurite outgrowth in hippocampal neurons, enhances the cell surface expression of 2 NMDA receptor subunits GRIN1 and GRIN2A, and may play a role in redistributing DLG4 to the cell periphery.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LRFN2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Heterozygous deletion of the LRFN2 gene is associated with working memory deficits Thevenon J , et al. (2015) No -
3 Positive Association Genome-wide association study of antisocial personality disorder Rautiainen MR , et al. (2016) No -
4 Primary Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice Morimura N , et al. (2017) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Wang J et al. (2023) Yes -
7 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.740A>T p.Asn247Ile missense_variant - - - 28604739 Morimura N , et al. (2017)
c.1286C>A p.Ser429Tyr missense_variant - - - 28604739 Morimura N , et al. (2017)
c.1462G>A p.Asp488Asn missense_variant - - - 28604739 Morimura N , et al. (2017)
c.210G>C p.Gln70His missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
- - copy_number_loss Familial Maternal Multiplex 26486473 Thevenon J , et al. (2015)
c.565G>A p.Ala189Thr missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.698C>T p.Pro233Leu missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.797G>T p.Gly266Val missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.1009G>A p.Ala337Thr missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.1418A>T p.Asn473Ile missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.2308G>A p.Asp770Asn missense_variant Unknown - - 28604739 Morimura N , et al. (2017)
c.983G>A p.Arg328His missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1850G>A p.Arg617His missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1229G>A p.Gly410Glu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1160G>A p.Ser387Asn missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1386G>C p.Glu462Asp missense_variant Familial - Simplex 28604739 Morimura N , et al. (2017)
c.643del p.Asp215IlefsTer12 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.821G>A p.Arg274His missense_variant Familial Paternal Simplex 28604739 Morimura N , et al. (2017)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 27598967 Rautiainen MR , et al. (2016)
SFARI Gene score
2

Strong Candidate

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

Reports Added
[New Scoring Scheme]
7/1/2017
icon
4

Increased from to 4

Description

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

Krishnan Probability Score

Score 0.49659756478073

Ranking 2561/25841 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 0.11746063718849

Ranking 7693/18225 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 0.53561427031754

Ranking 529/18665 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 0.14900977509196

Ranking 5206/20870 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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