Human Gene Module / Chromosome 11 / KIRREL3

KIRREL3Kin of IRRE like 3 (Drosophila)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 19
Rare Variants / Common Variants
33 / 0
Aliases
KIRREL3, KIRRE,  MRD4,  NEPH2,  PRO4502
Associated Syndromes
-
Chromosome Band
11q24.2
Associated Disorders
-
Relevance to Autism

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Molecular Function

The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. Mutations in this gene are associated with mental retardation autosomal dominant type 4 (MRD4; OMIM 612581).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KIRREL3 (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability Bhalla K , et al. (2008) No -
2 Primary Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries Talkowski ME , et al. (2012) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Recent Recommendation Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference Choi SY , et al. (2015) No -
6 Recent Recommendation The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus Martin EA , et al. (2015) No -
7 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
8 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
10 Recent Recommendation Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice Martin EA , et al. (2017) No -
11 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
12 Recent Recommendation Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications Kalsner L , et al. (2017) Yes -
13 Support Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice Hisaoka T , et al. (2018) No -
14 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
15 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
16 Support - Hildebrand MS et al. (2020) No DD
17 Recent Recommendation Kirrel3-Mediated Synapse Formation Is Attenuated by Disease-Associated Missense Variants Taylor MR et al. (2020) No -
18 Support - Zhou X et al. (2022) Yes -
19 Support - Hu C et al. (2023) Yes -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 22521361 Talkowski ME , et al. (2012)
- - translocation Unknown - Unknown 19012874 Bhalla K , et al. (2008)
c.55+85244T>A - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.134G>A p.Gly45Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.482G>A p.Arg161His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.134-1G>A - splice_site_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1276C>T p.Gln426Ter stop_gained Familial Paternal - 37007974 Hu C et al. (2023)
c.614G>A p.Arg205Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.722C>T p.Ser241Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1074G>T p.Trp358Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1282C>A p.Gln428Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1337C>T p.Pro446Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.482G>A p.Arg161His missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.775C>T p.Gln259Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2186G>T p.Ser729Ile missense_variant Unknown - - 32345733 Hildebrand MS et al. (2020)
c.118C>T p.Arg40Trp missense_variant Unknown - Unknown 19012874 Bhalla K , et al. (2008)
c.1949G>A p.Arg650His missense_variant De novo - Multiplex 30504930 Guo H , et al. (2018)
c.1177G>A p.Ala393Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1178C>T p.Ala393Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1007G>A p.Arg336Gln missense_variant Unknown - Unknown 19012874 Bhalla K , et al. (2008)
c.2191G>A p.Val731Ile missense_variant Unknown - Unknown 19012874 Bhalla K , et al. (2008)
c.2019G>A p.Met673Ile missense_variant De novo - Simplex 32503885 Taylor MR et al. (2020)
c.482G>A p.Arg161His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.655G>T p.Val219Leu missense_variant Familial Paternal - 29271092 Kalsner L , et al. (2017)
c.88G>A p.Val30Met missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.908T>C p.Val303Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1566G>T p.Lys522Asn missense_variant Familial Paternal - 29271092 Kalsner L , et al. (2017)
c.2199G>C p.Lys733Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.513C>G p.His171Gln missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1177G>A p.Ala393Thr missense_variant Familial Maternal Multiplex 29271092 Kalsner L , et al. (2017)
c.1231G>C p.Glu411Gln missense_variant Familial Maternal Multiplex 29271092 Kalsner L , et al. (2017)
c.1238C>T p.Thr413Ile missense_variant Familial Paternal Multiplex 29271092 Kalsner L , et al. (2017)
c.1685G>T p.Arg562Leu missense_variant Familial Both parents Simplex 30675382 Leblond CS , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified six rare variants in KIRREL3 from 90 ASD cases (6.7%) compared to 2.0% in the ExAC database (P = 0.001); the statistical enrichment of rare KIRREL3 variants in ASD cases remained significant after multiple comparisons correction. Kirrel3-/-mice were found to exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviors, and sensory abnormalities, as well as hyperactivity, in Hisaoka et al., 2018.

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.

7/1/2020
2
icon
2

Score remained at 2

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified six rare variants in KIRREL3 from 90 ASD cases (6.7%) compared to 2.0% in the ExAC database (P = 0.001); the statistical enrichment of rare KIRREL3 variants in ASD cases remained significant after multiple comparisons correction. Kirrel3-/-mice were found to exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviors, and sensory abnormalities, as well as hyperactivity, in Hisaoka et al., 2018.

Reports Added
[Kirrel3-Mediated Synapse Formation Is Attenuated by Disease-Associated Missense Variants2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified six rare variants in KIRREL3 from 90 ASD cases (6.7%) compared to 2.0% in the ExAC database (P = 0.001); the statistical enrichment of rare KIRREL3 variants in ASD cases remained significant after multiple comparisons correction. Kirrel3-/-mice were found to exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviors, and sensory abnormalities, as well as hyperactivity, in Hisaoka et al., 2018.

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

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified six rare variants in KIRREL3 from 90 ASD cases (6.7%) compared to 2.0% in the ExAC database (P = 0.001); the statistical enrichment of rare KIRREL3 variants in ASD cases remained significant after multiple comparisons correction. Kirrel3-/-mice were found to exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviors, and sensory abnormalities, as well as hyperactivity, in Hisaoka et al., 2018.

Reports Added
[Both rare and common genetic variants contribute to autism in the Faroe Islands.2019]
10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified six rare variants in KIRREL3 from 90 ASD cases (6.7%) compared to 2.0% in the ExAC database (P = 0.001); the statistical enrichment of rare KIRREL3 variants in ASD cases remained significant after multiple comparisons correction. Kirrel3-/-mice were found to exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviors, and sensory abnormalities, as well as hyperactivity, in Hisaoka et al., 2018.

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Reports Added
[Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice.2017]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Reports Added
[Genome-wide characteristics of de novo mutations in autism2016]
10/1/2015
icon
3

Increased from to 3

Description

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Krishnan Probability Score

Score 0.5004418142075

Ranking 2080/25841 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 0.97750578099196

Ranking 2204/18225 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 0.41377428663702

Ranking 297/18665 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 0.35359807573742

Ranking 1969/20870 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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