Human Gene Module / Chromosome 7 / RELN

RELNReelin

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
29 / 54
Rare Variants / Common Variants
166 / 9
Aliases
RELN, PRO1598,  RL
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Chromosome Band
7q22.1
Associated Disorders
EPS, DD/NDD, ID
Relevance to Autism

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Molecular Function

This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Reports related to RELN (54 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Proteins of the CNR family are multiple receptors for Reelin. Senzaki K , et al. (1999) No -
2 Primary Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Persico AM , et al. (2001) Yes -
3 Negative Association Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism. Krebs MO , et al. (2002) Yes -
4 Negative Association Analysis of reelin as a candidate gene for autism. Bonora E , et al. (2003) Yes -
5 Negative Association Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network. Devlin B , et al. (2004) Yes -
6 Negative Association Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Li J , et al. (2004) Yes -
7 Positive Association Analysis of the RELN gene as a genetic risk factor for autism. Skaar DA , et al. (2004) Yes -
8 Positive Association Association of Reelin gene polymorphisms with autism. Serajee FJ , et al. (2005) Yes -
9 Recent Recommendation Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling. Pla R , et al. (2006) No -
10 Recent Recommendation Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography. Nogi T , et al. (2006) No -
11 Recent Recommendation NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. Groc L , et al. (2007) No -
12 Positive Association The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Li H , et al. (2007) Yes -
13 Recent Recommendation Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control sys... Balthazart J , et al. (2008) No -
14 Recent Recommendation Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins. Barr AM , et al. (2008) No -
15 Recent Recommendation Neocortical RELN promoter methylation increases significantly after puberty. Lintas C and Persico AM (2009) No -
16 Positive Association Polymorphisms of candidate genes in Slovak autistic patients. Kelemenova S , et al. (2010) Yes -
17 Positive Association Linkage and candidate gene studies of autism spectrum disorders in European populations. Holt R , et al. (2010) Yes -
18 Negative Association No significant association between RELN polymorphism and autism in case-control and family-based association study in Chinese Han population. He Y , et al. (2010) Yes -
19 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
20 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
21 Recent Recommendation Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2... Iafrati J , et al. (2013) No -
22 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
23 Positive Association Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population. Fu X , et al. (2014) Yes -
24 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. Cukier HN , et al. (2014) Yes -
25 Recent Recommendation Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Zhubi A , et al. (2014) No -
26 Positive Association Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis. Wang Z , et al. (2014) Yes -
27 Recent Recommendation Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment. Kupferman JV , et al. (2014) No -
28 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
29 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
30 Recent Recommendation LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation. Telese F , et al. (2015) No -
31 Support Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Dazzo E , et al. (2015) No -
32 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
33 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
34 Recent Recommendation Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects. Lintas C , et al. (2016) No -
35 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
36 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No DD, ID, epilepsy/seizures
37 Recent Recommendation Reelin-Haploinsufficiency Disrupts the Developmental Trajectory of the E/I Balance in the Prefrontal Cortex. Bouamrane L , et al. (2017) No -
38 Recent Recommendation The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression. Whittaker DE , et al. (2017) No -
39 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
40 Recent Recommendation The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression. Lammert DB , et al. (2017) No -
41 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
42 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
43 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No Hypotonia, lissencephaly
44 Positive Association Two single-nucleotide polymorphisms of the RELN gene and symptom-based and developmental deficits among children and adolescents with autistic spec... Wang GF , et al. (2018) Yes -
45 Support Rare RELN variants affect Reelin-DAB1 signal transduction in autism spectrum disorder. Snchez-Snchez SM , et al. (2018) Yes -
46 Positive Association A pilot Indian family-based association study between dyslexia and Reelin pathway genes, DCDC2 and ROBO1, identifies modest association with a tria... Devasenapathy S , et al. (2018) No -
47 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
48 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No DD, ID
49 Support Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients. Balicza P , et al. (2019) Yes Familial temporal lobe epilepsy-7, lissencephaly 2
50 Support Mutations in ASH1L confer susceptibility to Tourette syndrome. Liu S , et al. (2019) No -
51 Support Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map Bayraktar OA et al. (2020) No -
52 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
53 Highly Cited A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. D'Arcangelo G , et al. (1995) No -
54 Highly Cited Role of reelin in the control of brain development. Curran T and D'Arcangelo G (1998) No -
Rare Variants   (166)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - intron_variant - - - 20442744 Holt R , et al. (2010)
C>T - intron_variant - - - 17955477 Li H , et al. (2007)
c.9606-57C>T - intron_variant - - - 16311013 Serajee FJ , et al. (2005)
- - frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.6672-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.6268G>T p.Glu2090Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1013T>G p.Val338Gly missense_variant - - - 14515139 Bonora E , et al. (2003)
c.1888A>C p.Ser630Arg missense_variant - - - 14515139 Bonora E , et al. (2003)
c.2989C>G p.Leu997Val missense_variant - - - 14515139 Bonora E , et al. (2003)
c.10321C>T p.Arg3441Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3839G>A p.Gly1280Glu missense_variant - - - 14515139 Bonora E , et al. (2003)
c.5399C>T p.Arg1742Trp missense_variant - - - 14515139 Bonora E , et al. (2003)
c.7438G>A p.Gly2480Ser missense_variant - - - 14515139 Bonora E , et al. (2003)
c.2989C>G p.Leu997Val missense_variant - - - 16311013 Serajee FJ , et al. (2005)
c.331G>A p.Gly111Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.331G>C p.Gly111Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.490C>T p.Arg164Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1328G>T p.Gly443Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2737C>T p.Arg913Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2869G>A p.Gly957Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.396C>A p.His132Gln missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.3028C>T p.Arg1010Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3158G>A p.Gly1053Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3338G>A p.Gly1113Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3592C>A p.Arg1198Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3953C>T p.Pro1318Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4019C>T p.Pro1340Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4160G>A p.Arg1387Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4216G>A p.Val1406Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4727G>A p.Arg1576Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4945C>T p.Arg1649Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5225G>A p.Arg1742Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5344C>T p.Arg1782Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6032G>A p.Arg2011His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6353C>T p.Pro2118Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6458G>A p.Gly2153Asp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6575G>C p.Arg2192Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6632G>A p.Arg2211His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6875G>A p.Arg2292His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6925G>A p.Asp2309Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7867G>A p.Val2623Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7915C>T p.Arg2639Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7916G>A p.Arg2639His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8261T>G p.Ile2754Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8330A>T p.Gln2777Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8792G>A p.Gly2931Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8863C>T p.Arg2955Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8899C>T p.Arg2967Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8912G>A p.Arg2971Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.9715G>A p.Gly3239Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2989C>G p.Leu997Val missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.10025C>T p.Thr3342Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10123G>A p.Ala3375Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10225C>T p.Arg3409Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10358G>A p.Arg3453Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.9619C>T p.Arg3207Cys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1900C>T p.Arg634Ter stop_gained De novo NA Simplex 31673123 Liu S , et al. (2019)
c.4726C>T p.Arg1576Ter stop_gained De novo NA - 28191889 Stessman HA , et al. (2017)
c.7399C>T p.Gln2467Ter stop_gained De novo NA - 28191889 Stessman HA , et al. (2017)
c.1249C>T p.Gln417Ter stop_gained De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.4354G>A p.Asp1452Asn missense_variant De novo NA - 31134136 Balicza P , et al. (2019)
c.3338G>A p.Gly1113Glu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.6461A>G p.Tyr2154Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.8404G>A p.Gly2802Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7593del p.Trp2531CysfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.545-1G>T - splice_site_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.425G>A p.Ser142Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.7966G>A p.Asp2656Asn missense_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.7399C>T p.Gln2467Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4019C>T p.Pro1340Leu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4160G>A p.Arg1387Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.9329G>A p.Arg3110Gln missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1913C>T p.Pro638Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1913C>T p.Pro638Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.3711+2T>C - splice_site_variant - Both parents Multiplex 28940097 Anazi S , et al. (2017)
c.10358G>A p.Arg3453Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5180G>A p.Arg1727Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.9979G>T p.Ala3327Ser missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.9938A>G p.Gln3313Arg missense_variant Familial Paternal - 30945278 Jiao Q , et al. (2019)
c.1803G>T p.Trp601Cys missense_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.9526G>A p.Glu3176Lys missense_variant Unknown - Multiplex 26046367 Dazzo E , et al. (2015)
c.467G>A p.Arg156His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.761G>T p.Gly254Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2015C>T p.Pro672Leu missense_variant Familial Paternal - 31134136 Balicza P , et al. (2019)
c.1235C>T p.Ser412Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1336G>C p.Glu446Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2351C>T p.Thr784Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2932A>G p.Thr978Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6311G>A p.Arg2104His missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.5954C>A p.Ser1985Tyr missense_variant De novo NA Multiplex 25621899 Yuen RK , et al. (2015)
c.8915A>C p.Lys2972Thr missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.3565G>A p.Ala1189Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3712A>C p.Asn1238His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4379C>A p.Pro1460His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4972G>A p.Val1658Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5711C>T p.Thr1904Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6205T>C p.Cys2069Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6458G>A p.Gly2153Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6520G>A p.Glu2174Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6647G>A p.Arg2216Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6925G>A p.Asp2309Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7114G>A p.Val2372Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7184T>C p.Ile2395Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7634C>T p.Ala2545Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8499G>T p.Arg2833Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8944G>A p.Asp2982Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5414_5417del p.Lys1805ThrfsTer23 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.6868C>T p.Arg2290Cys missense_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.10120A>G p.Ile3374Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.10276G>A p.Val3426Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7565T>C p.Phe2522Ser missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.4019C>T p.Pro1340Leu missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.6925G>A p.Asp2309Asn missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5464G>A p.Gly1822Ser missense_variant Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.666del p.Cys222Ter frameshift_variant Familial Maternal Simplex 33004838 Wang T et al. (2020)
c.9226dup p.Tyr3076LeufsTer3 frameshift_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.2252A>C p.Lys751Thr missense_variant Familial Maternal Simplex 26544041 Zhang Y , et al. (2015)
c.2926G>A p.Glu976Lys missense_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.10276G>A p.Val3426Ile missense_variant Familial Paternal Simplex 26544041 Zhang Y , et al. (2015)
c.2168A>G p.Tyr723Cys missense_variant Familial Maternal Multiplex 26046367 Dazzo E , et al. (2015)
c.3477C>A p.Asn1159Lys missense_variant Familial Paternal Simplex 14515139 Bonora E , et al. (2003)
c.5225G>A p.Arg1742Gln missense_variant Familial Paternal Simplex 14515139 Bonora E , et al. (2003)
c.5284G>A p.Val1762Ile missense_variant Familial Paternal Simplex 14515139 Bonora E , et al. (2003)
c.9715G>A p.Gly3239Arg missense_variant Familial Maternal Simplex 28867142 Krupp DR , et al. (2017)
c.7044C>T p.Gly2348= missense_variant Familial Paternal Multiplex 14515139 Bonora E , et al. (2003)
c.3548A>G p.Tyr1183Cys missense_variant Familial Maternal - 26845707 Alvarez-Mora MI , et al. (2016)
c.2531C>T p.Pro844Leu missense_variant Familial - Extended multiplex 26046367 Dazzo E , et al. (2015)
c.2288A>G p.Asp763Gly missense_variant Familial - Multi-generational 26046367 Dazzo E , et al. (2015)
c.2392C>A p.His798Asn missense_variant Familial - Multi-generational 26046367 Dazzo E , et al. (2015)
c.1108G>C p.Gly370Arg missense_variant Familial Maternal Multiplex 14515139 Bonora E , et al. (2003)
c.763C>T p.Arg255Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.763C>T p.Arg255Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7605C>T p.Asn2535= missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7538C>G p.Ser2513Cys missense_variant Familial Paternal - 29969175 Snchez-Snchez SM , et al. (2018)
c.7634C>T p.Ala2545Val missense_variant Familial Maternal - 29969175 Snchez-Snchez SM , et al. (2018)
c.8347G>T p.Gly2783Cys missense_variant Familial - Multi-generational 26046367 Dazzo E , et al. (2015)
c.3477C>A p.Asn1159Lys missense_variant Familial Maternal Multiplex 14515139 Bonora E , et al. (2003)
c.5156C>T p.Ser1719Leu missense_variant Familial Maternal Multiplex 14515139 Bonora E , et al. (2003)
c.5156C>T p.Ser1719Leu missense_variant Familial Paternal Multiplex 14515139 Bonora E , et al. (2003)
c.5284G>A p.Val1762Ile missense_variant Familial Maternal Multiplex 14515139 Bonora E , et al. (2003)
c.8327T>C p.Val2776Ala missense_variant Familial Paternal Multiplex 14515139 Bonora E , et al. (2003)
c.1231C>A p.Leu411Ile missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1566G>C p.Leu522Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2464A>G p.Arg822Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4228G>A p.Glu1410Lys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4739C>T p.Pro1580Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5225G>A p.Arg1742Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5711C>T p.Thr1904Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6169C>G p.Leu2057Val missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6726G>C p.Arg2242Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6734C>G p.Pro2245Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6874C>T p.Arg2292Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6925G>A p.Asp2309Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7114G>A p.Val2372Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10120A>G p.Ile3374Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10136C>G p.Pro3379Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10276G>A p.Val3426Ile missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10316G>A p.Arg3439Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1231C>A p.Leu411Ile missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.5179C>T p.Arg1727Trp missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.6925G>A p.Asp2309Asn missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.3249del p.Trp1083CysfsTer10 frameshift_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2015C>T p.Pro672Leu missense_variant Familial Maternal Multi-generational 26046367 Dazzo E , et al. (2015)
c.668del p.Asn223ThrfsTer29 frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9841del p.Ala3281GlnfsTer11 frameshift_variant Familial Both parents Simplex 27848944 Trujillano D , et al. (2016)
c.3839G>A p.Gly1280Glu missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
N/A N/A trinucleotide_repeat_microsatellite_feature, 5_prime_UTR_variant - - - 15558079 Skaar DA , et al. (2004)
N/A N/A trinucleotide_repeat_microsatellite_feature, 5_prime_UTR_variant - - - 20436377 Kelemenova S , et al. (2010)
c.-24_-22GGC(4_10) - trinucleotide_repeat_microsatellite_feature, 5_prime_UTR_variant - - - 11317216 Persico AM , et al. (2001)
c.9606-57T>C - intron_variant - - - 29753726 Wang GF , et al. (2018)
c.8046T>C p.(=) synonymous_variant - - - 29753726 Wang GF , et al. (2018)
c.9606-57T>C C/T intron_variant - - - 16311013 Serajee FJ , et al. (2005)
c.1075G>A p.Val359Ile missense_variant - - - 24385848 Fu X , et al. (2014)
c.2989C>G p.Val997Leu missense_variant - - - 24453138 Wang Z , et al. (2014)
c.2989C>G p.Val997Leu missense_variant - - - 16311013 Serajee FJ , et al. (2005)
SFARI Gene score
1

High Confidence

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

10/1/2020
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map2020]
10/1/2019
1
icon
1

Score remained at 1

New Scoring Scheme
Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Mutations in ASH1L confer susceptibility to Tourette syndrome.2019] [New Scoring Scheme]
7/1/2019
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients.2019]
4/1/2019
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
1/1/2019
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[A pilot Indian family-based association study between dyslexia and Reelin pathway genes, DCDC2 and ROBO1, identifies modest association with a tria...2018]
7/1/2018
1.1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Rare RELN variants affect Reelin-DAB1 signal transduction in autism spectrum disorder.2018]
4/1/2018
1
icon
1.1

Score remained at 1.1

Description

1

Reports Added
[Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.2015] [Two single-nucleotide polymorphisms of the RELN gene and symptom-based and developmental deficits among children and adolescents with autistic spec...2018]
10/1/2017
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR ? 0.05, meaning that this gene had a ? 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Expanding the genetic heterogeneity of intellectual disability.2017] [Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
4/1/2017
1
icon
1

Score remained at 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells.

Reports Added
[Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.2001] [Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.2002] [Analysis of reelin as a candidate gene for autism.2003] [Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.2004] [Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.2004] [Analysis of the RELN gene as a genetic risk factor for autism.2004] [Association of Reelin gene polymorphisms with autism.2005] [The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population.2007] [Polymorphisms of candidate genes in Slovak autistic patients.2010] [Linkage and candidate gene studies of autism spectrum disorders in European populations.2010] [No significant association between RELN polymorphism and autism in case-control and family-based association study in Chinese Han population.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population.2014] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.1995] [Role of reelin in the control of brain development.1998] [Proteins of the CNR family are multiple receptors for Reelin.1999] [Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling.2006] [Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography.2006] [NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin.2007] [Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control sys...2008] [Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins.2008] [Neocortical RELN promoter methylation increases significantly after puberty.2009] [Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2...2013] [Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.2014] [Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment.2014] [LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Reelin-Haploinsufficiency Disrupts the Developmental Trajectory of the E/I Balance in the Prefrontal Cortex.2017] [The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression.2017] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression.2017]
1/1/2017
2
icon
1

Decreased from 2 to 1

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

Reports Added
[Reelin-Haploinsufficiency Disrupts the Developmental Trajectory of the E/I Balance in the Prefrontal Cortex.2017] [The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression.2017] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
2
icon
2

Decreased from 2 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
4/1/2016
2
icon
2

Decreased from 2 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.2001] [Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.2002] [Analysis of reelin as a candidate gene for autism.2003] [Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.2004] [Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.2004] [Analysis of the RELN gene as a genetic risk factor for autism.2004] [Association of Reelin gene polymorphisms with autism.2005] [The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population.2007] [Polymorphisms of candidate genes in Slovak autistic patients.2010] [Linkage and candidate gene studies of autism spectrum disorders in European populations.2010] [No significant association between RELN polymorphism and autism in case-control and family-based association study in Chinese Han population.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population.2014] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.1995] [Role of reelin in the control of brain development.1998] [Proteins of the CNR family are multiple receptors for Reelin.1999] [Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling.2006] [Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography.2006] [NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin.2007] [Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control sys...2008] [Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins.2008] [Neocortical RELN promoter methylation increases significantly after puberty.2009] [Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2...2013] [Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.2014] [Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment.2014] [LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.2001] [Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.2002] [Analysis of reelin as a candidate gene for autism.2003] [Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.2004] [Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.2004] [Analysis of the RELN gene as a genetic risk factor for autism.2004] [Association of Reelin gene polymorphisms with autism.2005] [The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population.2007] [Polymorphisms of candidate genes in Slovak autistic patients.2010] [Linkage and candidate gene studies of autism spectrum disorders in European populations.2010] [No significant association between RELN polymorphism and autism in case-control and family-based association study in Chinese Han population.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population.2014] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.1995] [Role of reelin in the control of brain development.1998] [Proteins of the CNR family are multiple receptors for Reelin.1999] [Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling.2006] [Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography.2006] [NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin.2007] [Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control sys...2008] [Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins.2008] [Neocortical RELN promoter methylation increases significantly after puberty.2009] [Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2...2013] [Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.2014] [Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment.2014] [LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016]
4/1/2015
2
icon
2

Decreased from 2 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.2015]
1/1/2015
2
icon
2

Decreased from 2 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015]
10/1/2014
3
icon
2

Decreased from 3 to 2

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists. A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified RELN as a gene meeting high statistical significance with a 0.01

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists.

Reports Added
[A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.1995] [Role of reelin in the control of brain development.1998] [Proteins of the CNR family are multiple receptors for Reelin.1999] [Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.2001] [Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.2002] [Analysis of reelin as a candidate gene for autism.2003] [Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.2004] [Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.2004] [Analysis of the RELN gene as a genetic risk factor for autism.2004] [Association of Reelin gene polymorphisms with autism.2005] [Layer acquisition by cortical GABAergic interneurons is independent of Reelin signaling.2006] [Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography.2006] [NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin.2007] [The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population.2007] [Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control sys...2008] [Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins.2008] [Neocortical RELN promoter methylation increases significantly after puberty.2009] [Polymorphisms of candidate genes in Slovak autistic patients.2010] [Linkage and candidate gene studies of autism spectrum disorders in European populations.2010] [No significant association between RELN polymorphism and autism in case-control and family-based association study in Chinese Han population.2010] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2...2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population.2014] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.2014] [Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.2014] [Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment.2014]
4/1/2014
No data
icon
3

Increased from No data to 3

Description

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations (Persico et al., 2001), the Chinese Han population and Caucasian AGRE families. Several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations. Variable expression data also exists.

Krishnan Probability Score

Score 0.59647240907854

Ranking 436/25841 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 1

Ranking 15/18225 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 0.2518881696863

Ranking 144/18665 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
Larsen Cumulative Evidence Score

Score 97.5

Ranking 9/461 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.
Original Source
Zhang D Score

Score 0.64382315238865

Ranking 19/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
EPHB3 EPH receptor B3 Human Protein Binding 2049 P54753
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