Human Gene Module / Chromosome 7 / CNTNAP2

CNTNAP2contactin associated protein-like 2

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
26 / 57
Rare Variants / Common Variants
85 / 30
Aliases
CNTNAP2, CDFE,  NRXN4,  CASPR2,  DKFZp781D1846
Associated Syndromes
Cortical dysplasia-focal epilepsy syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
7q35-q36.1
Associated Disorders
ID, ADHD, EPS, EP, ASD
Relevance to Autism

Several studies have found a genetic association of the CNTNAP2 gene with autism. Among these, one study (Li et al., 2010) found positive association with the Chinese Han population. In addition, rare variants in the CNTNAP2 gene, including deletions and nonsynonymous changes, are also suggested to play a role in autism, ID, DD and language impairment. Interestingly, positive associations with CNTNAP2 and selective mutism, epilepsy and specific language impairment have also been found.

Molecular Function

This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein is localized at the juxtaparanodes of myelinated axons and associated with potassium channels.

Reports related to CNTNAP2 (57 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Poliak S , et al. (2000) No -
2 Support CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Verkerk AJ , et al. (2003) No TS (2/3 cases), MR (2/3 cases)
3 Support Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. Strauss KA , et al. (2006) No ID, ADHD, ASD, epilepsy/seizures
4 Support CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Friedman JI , et al. (2007) No Epilepsy
5 Positive Association Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Alarcn M , et al. (2008) Yes -
6 Primary A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Arking DE , et al. (2008) Yes -
7 Support Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Bakkaloglu B , et al. (2008) Yes -
8 Positive Association A functional genetic link between distinct developmental language disorders. Vernes SC , et al. (2008) Yes -
9 Recent Recommendation Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. Horresh I , et al. (2008) No -
10 Recent Recommendation Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS. Oiso S , et al. (2009) No -
11 Support Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Poot M , et al. (2009) Yes -
12 Support CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D... Zweier C , et al. (2009) No Epilepsy
13 Recent Recommendation Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. Horresh I , et al. (2010) No -
14 Recent Recommendation Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. Tan GC , et al. (2010) No -
15 Positive Association Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population. Li X , et al. (2010) Yes -
16 Recent Recommendation Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. Mefford HC , et al. (2010) No ASD
17 Recent Recommendation Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Scott-Van Zeeland AA , et al. (2010) No -
18 Support Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case. Petrin AL , et al. (2010) Yes -
19 Recent Recommendation A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-relat... Stein MB , et al. (2011) No -
20 Positive Association CNTNAP2 variants affect early language development in the general population. Whitehouse AJ , et al. (2011) Yes -
21 Support Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Nord AS , et al. (2011) Yes -
22 Support Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
23 Recent Recommendation Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. Gregor A , et al. (2011) No -
24 Recent Recommendation Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Peagarikano O , et al. (2011) No -
25 Recent Recommendation Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental... Mikhail FM , et al. (2011) No ID
26 Support Rare copy number variants are an important cause of epileptic encephalopathies. Mefford HC , et al. (2011) No ID, ASD
27 Support Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi... Lesca G , et al. (2012) No ADHD
28 Recent recommendation Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization. Laffin JJ , et al. (2012) No -
29 Positive association Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Anney R , et al. (2012) Yes -
30 Recent Recommendation Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. Anderson GR , et al. (2012) No -
31 Support Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay. Al-Murrani A , et al. (2012) No -
32 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
33 Negative Association Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2. Toma C , et al. (2013) Yes -
34 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
35 Recent Recommendation CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study. Clemm von Hohenberg C , et al. (2013) No -
36 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
37 Support Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech. Worthey EA , et al. (2013) No -
38 Positive Association Defining the contribution of CNTNAP2 to autism susceptibility. Sampath S , et al. (2013) Yes -
39 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families. Egger G , et al. (2014) Yes -
40 Support Diagnostic whole genome sequencing and split-read mapping for nucleotide resolution breakpoint identification in CNTNAP2 deficiency syndrome. Watson CM , et al. (2014) No Epilepsy
41 Positive association Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach. Chiocchetti AG , et al. (2014) Yes -
42 Positive association A candidate gene association study further corroborates involvement of contactin genes in autism. Poot M (2014) Yes -
43 Negative association No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti... Murdoch JD , et al. (2015) Yes -
44 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Epilepsy/seizures
45 Negative association CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches. Werling AM , et al. (2015) Yes -
46 Recent recommendation Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. Hoffman EJ , et al. (2016) No -
47 Support Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment. Rodenas-Cuadrado P , et al. (2016) Yes -
48 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
49 Positive association Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder. Nascimento PP , et al. (2016) Yes -
50 Support Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. Lee IS , et al. (2016) No -
51 Support Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and... Smogavec M , et al. (2016) No -
52 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
53 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No -
54 Support Associations between the CNTNAP2 gene, dorsolateral prefrontal cortex, and cognitive performance on the Stroop task. Zhu B , et al. (2016) No -
55 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Chen XS , et al. (2017) No -
56 Support Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration. Ross LA , et al. (2017) No -
57 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
Rare Variants   (85)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - complex_structural_alteration Familial Paternal Multi-generational 12809671 Verkerk AJ , et al. (2003)
c.[3709delG];[3709delG] p.[Asp1237IlefsTer17];[Asp1237IlefsTer17] frameshift_variant;frameshift_variant Familial Both parents - 16571880 Strauss KA , et al. (2006)
- - copy_number_loss Unknown - Simplex 17646849 Friedman JI , et al. (2007)
- - copy_number_loss Familial Paternal Multiplex 18179893 Alarcn M , et al. (2008)
c.1220A>G p.Asn407Ser missense_variant - - - 18179895 Bakkaloglu B , et al. (2008)
c.1252A>G p.Asn418Asp missense_variant - - - 18179895 Bakkaloglu B , et al. (2008)
c.2147A>G p.Tyr716Cys missense_variant - - - 18179895 Bakkaloglu B , et al. (2008)
c.2191G>A p.Gly731Ser missense_variant Familial Paternal Simplex 18179895 Bakkaloglu B , et al. (2008)
c.2606T>C p.Ile869Thr missense_variant Familial Paternal Multiplex 18179895 Bakkaloglu B , et al. (2008)
c.2606T>C p.Ile869Thr missense_variant Familial Maternal Simplex 18179895 Bakkaloglu B , et al. (2008)
c.2606T>C p.Ile869Thr missense_variant Familial Paternal Simplex 18179895 Bakkaloglu B , et al. (2008)
c.2717G>A p.Arg906His missense_variant Familial Paternal Multiplex 18179895 Bakkaloglu B , et al. (2008)
c.3356G>A p.Arg1119His missense_variant Familial Paternal Multiplex 18179895 Bakkaloglu B , et al. (2008)
c.3385G>C p.Asp1129His missense_variant Familial Paternal Multiplex 18179895 Bakkaloglu B , et al. (2008)
c.3679G>A p.Ala1227Thr missense_variant Familial Maternal & paternal Multi-generational 18179895 Bakkaloglu B , et al. (2008)
c.3758T>C p.Ile1253Thr missense_variant Familial Maternal Multiplex 18179895 Bakkaloglu B , et al. (2008)
c.3833C>T p.Thr1278Ile missense_variant Familial Maternal Simplex 18179895 Bakkaloglu B , et al. (2008)
- - complex_structural_alteration De novo - Simplex 19582487 Poot M , et al. (2009)
- - copy_number_loss Familial Both parents Multiplex 19896112 Zweier C , et al. (2009)
- - copy_number_loss Familial Maternal Simplex 19896112 Zweier C , et al. (2009)
IVS10-1G>T - splice_site_variant Familial Paternal Simplex 19896112 Zweier C , et al. (2009)
- - copy_number_loss Familial Paternal - 20502679 Mefford HC , et al. (2010)
- - copy_number_loss Unknown - Simplex 21108403 Petrin AL , et al. (2010)
- - copy_number_loss Familial Maternal - 21448237 Nord AS , et al. (2011)
c.824A>G p.His275Arg missense_variant Familial - Simplex 21572417 O'Roak BJ , et al. (2011)
G1083A N/A splice_site_variant Familial Paternal - 21827697 Gregor A , et al. (2011)
G1083A N/A splice_site_variant Familial Maternal - 21827697 Gregor A , et al. (2011)
c.1175_1176dup p.Asp393ArgfsTer51 frameshift_variant Familial Paternal - 21827697 Gregor A , et al. (2011)
c.2153G>A p.Trp718Ter stop_gained - - - 21827697 Gregor A , et al. (2011)
- - copy_number_loss Familial Maternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss Familial Maternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss De novo - - 21827697 Gregor A , et al. (2011)
- - copy_number_loss - - - 22031302 Mikhail FM , et al. (2011)
- - copy_number_loss Familial Both parents Multiplex 22190369 Mefford HC , et al. (2011)
- - copy_number_gain Familial Maternal Unknown 22738016 Lesca G , et al. (2012)
- - copy_number_loss Unknown - Simplex 22766611 Laffin JJ , et al. (2012)
c.98_550del p.Gln33_Trp184delinsArg copy_number_loss Familial Maternal Multiplex 23074684 Al-Murrani A , et al. (2012)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
c.1276C>A p.Leu426Ile missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.1448G>A p.Arg483Gln missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.511C>T p.Arg171Cys missense_variant Unknown - Unknown 24083349 Worthey EA , et al. (2013)
c.3714_3717insTTG - intron_variant Unknown - Unknown 24083349 Worthey EA , et al. (2013)
- - copy_number_loss Unknown - - 24643514 Egger G , et al. (2014)
- - copy_number_loss Familial Both parents Multi-generational 25045150 Watson CM , et al. (2014)
c.-215G>A - 2KB_upstream_variant Familial Paternal Simplex 25224256 Chiocchetti AG , et al. (2014)
c.158C>G p.Ser53Cys missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.338A>G p.Tyr113Cys missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.416A>G p.Asn139Ser missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.824A>G p.His275Arg missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.963C>A p.Phe321Leu missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.1051G>A p.Ala351Thr missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2123T>C p.Val708Ala missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2205C>A p.Asn735Lys missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2288A>G p.Asp763Gly missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2476T>G p.Tyr826Asp missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2657C>T p.Thr886Ile missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.2698C>T p.Arg900Trp missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3080G>C p.Arg1027Thr missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3131C>T p.Pro1044Leu missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3470T>C p.Val1157Ala missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3674C>T p.Ser1225Leu missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3758T>C p.Ile1253Thr missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.860G>A p.Ser287Asn missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
c.3305T>C p.Val1102Ala missense_variant Unknown - Simplex 25621974 Murdoch JD , et al. (2015)
- - copy_number_loss;copy_number_loss Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
- - copy_number_loss;copy_number_loss Familial Both parents Multiplex 26843181 Rodenas-Cuadrado P , et al. (2016)
- p.Asp1073Val missense_variant Familial Paternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
- - copy_number_loss Familial Paternal Simplex 26985448 Lee IS , et al. (2016)
c.[1480G>T];[1480G>T] p.[Glu494Ter];[Glu494Ter] stop_gained;stop_gained Familial Both parents Simplex 27439707 Smogavec M , et al. (2016)
c.3046C>T p.Arg1016Ter copy_number_loss;stop_gained Familial - Simplex 27439707 Smogavec M , et al. (2016)
- - copy_number_loss;copy_number_loss Familial - Simplex 27439707 Smogavec M , et al. (2016)
c.2963delC p.Cys989AlafsTer45 copy_number_loss;frameshift_variant Familial - Multiplex 27439707 Smogavec M , et al. (2016)
- - copy_number_loss;copy_number_gain Familial - Possible multi-generational 27439707 Smogavec M , et al. (2016)
c.[2046C>A];[2046C>A] p.[Cys682Ter];[Cys682Ter] stop_gained;stop_gained Familial Both parents Multiplex 27439707 Smogavec M , et al. (2016)
delG - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
T>C - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.[1777+2T>C];[1777+2T>C] - splice_site_variant;splice_site_variant - - - 27864847 Parrini E , et al. (2016)
c.1105G>T p.Val369Leu missense_variant Familial Paternal Multiplex 28440294 Chen XS , et al. (2017)
c.152C>G p.Ser51Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1679C>G p.Pro560Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2396A>G p.Asn799Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2797T>C p.Phe933Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.653C>T p.Thr218Met missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
Common Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2099-26267A>G;c.587-26267A>G N/A intron_variant - - - 18179893 Alarcn M , et al. (2008)
c.208+18133A>T - intron_variant - - - 18179894 Arking DE , et al. (2008)
c.2099-73751C>T;c.587-73751C>T A/G intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-45850C>T;c.587-45850C>T - intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-26267A>G;c.587-26267A>G C/T intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-25545A>C;c.587-25545A>C G to T intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-24246C>T;c.587-24246C>T T to C intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-21038A>C;c.587-21038A>C C/A intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-18352A>G;c.587-18352A>G - intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-14838T>C;c.587-14838T>C G/A intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2099-3491T>C;c.587-3491T>C A to G intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.2255+959T>A;c.743+959T>A A/T intron_variant - - - 18987363 Vernes SC , et al. (2008)
c.1348+50804A>G - intron_variant - - - 20414140 Li X , et al. (2010)
c.2099-26267A>G;c.587-26267A>G N/A intron_variant - - - 21193173 Stein MB , et al. (2011)
c.1349-83693C>T G/A intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.2099-26267A>G;c.587-26267A>G C/T intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.2099-25545A>C;c.587-25545A>C G to T intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.2099-18352A>G;c.587-18352A>G - intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.2099-14838T>C;c.587-14838T>C G/A intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.2255+959T>A;c.743+959T>A A/G intron_variant - - - 21310003 Whitehouse AJ , et al. (2011)
c.97+308723T>C - intron_variant - - - 22843504 Anney R , et al. (2012)
c.2255+31322G>C;c.743+31322G>C G/C intron_variant - - - 24147096 Sampath S , et al. (2013)
c.2255+31088A>G;c.743+31088A>G - intron_variant - - - 24147096 Sampath S , et al. (2013)
c.-876A>G - 2KB_upstream_variant - - - 25224256 Chiocchetti AG , et al. (2014)
GCG[6]/GCG[7] - trinucleotide_repeat_microsatellite_feature - - - 25224256 Chiocchetti AG , et al. (2014)
c.403-21804C>T Allele 1, A; allele 2, G intron_variant - - - 25337070 Poot M (2014)
c.402+30643C>T - intron_variant - - - 25337070 Poot M (2014)
c.403-32955T>G A/C intron_variant - - - 25337070 Poot M (2014)
c.208+18133A>T - intron_variant - - - 26559825 Werling AM , et al. (2015)
c.208+18133A>T - intron_variant - - - 26909962 Nascimento PP , et al. (2016)
SFARI Gene score
2S

Strong Candidate, Syndromic

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Score Delta: Score remained at 2S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2015
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

1/1/2016
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Reports Added
[Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population.2010] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.2007] [Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.2012] [Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.2010] [A functional genetic link between distinct developmental language disorders.2008] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder.2016] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches.2015] [Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.2010] [Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.2006] [A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.2008] [Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization.2012] [Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.2008] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.2013] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-relat...2011] [Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS.2009] [Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach.2014] [Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.2010] [Diagnostic whole genome sequencing and split-read mapping for nucleotide resolution breakpoint identification in CNTNAP2 deficiency syndrome.2014] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.2011] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case.2010] [Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay.2012] [Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.2010] [Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.2009] [CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.2003] [Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment.2016] [Defining the contribution of CNTNAP2 to autism susceptibility.2013] [Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.2008] [Reduced transcript expression of genes affected by inherited and de novo CNVs in autism.2011] [Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.2008] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.2013] [Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.2016] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [CNTNAP2 variants affect early language development in the general population.2011] [Rare copy number variants are an important cause of epileptic encephalopathies.2011] [Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.2000]
1/1/2017
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

10/1/2014
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

10/1/2015
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

10/1/2016
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

10/1/2017
2S
icon
2S

Score remained at 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

4/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

4/1/2015
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

4/1/2016
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Reports Added
[Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population.2010] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.2007] [Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.2016] [Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.2006] [Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.2012] [Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells.2016] [Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.2010] [Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder.2016] [A functional genetic link between distinct developmental language disorders.2008] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.2010] [CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches.2015] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.2008] [Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization.2012] [Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.2008] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.2013] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-relat...2011] [Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS.2009] [Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach.2014] [Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.2010] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Diagnostic whole genome sequencing and split-read mapping for nucleotide resolution breakpoint identification in CNTNAP2 deficiency syndrome.2014] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.2011] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case.2010] [Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.2010] [Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay.2012] [Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.2009] [CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.2003] [Defining the contribution of CNTNAP2 to autism susceptibility.2013] [Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.2008] [Reduced transcript expression of genes affected by inherited and de novo CNVs in autism.2011] [Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.2008] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.2013] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment.2016] [CNTNAP2 variants affect early language development in the general population.2011] [Rare copy number variants are an important cause of epileptic encephalopathies.2011] [Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.2000] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012]
4/1/2017
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Reports Added
[Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population.2010] [Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.2000] [CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.2013] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.2007] [Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.2006] [Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.2012] [Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells.2016] [A functional genetic link between distinct developmental language disorders.2008] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches.2015] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.2008] [Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization.2012] [Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.2010] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.2008] [Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.2013] [Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder.2016] [Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and...2016] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-relat...2011] [Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS.2009] [Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.2010] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Diagnostic whole genome sequencing and split-read mapping for nucleotide resolution breakpoint identification in CNTNAP2 deficiency syndrome.2014] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.2011] [Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case.2010] [Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.2017] [Associations between the CNTNAP2 gene, dorsolateral prefrontal cortex, and cognitive performance on the Stroop task.2016] [Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.2010] [Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay.2012] [Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.2009] [Defining the contribution of CNTNAP2 to autism susceptibility.2013] [CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.2003] [Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.2008] [Reduced transcript expression of genes affected by inherited and de novo CNVs in autism.2011] [Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.2008] [Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment.2016] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.2010] [Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.2016] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [CNTNAP2 variants affect early language development in the general population.2011] [Rare copy number variants are an important cause of epileptic encephalopathies.2011] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012]
7/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Reports Added
[Diagnostic whole genome sequencing and split-read mapping for nucleotide resolution breakpoint identification in CNTNAP2 deficiency syndrome.2014] [Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.2000] [CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.2003] [Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.2006] [CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.2007] [Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.2008] [A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.2008] [Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.2008] [A functional genetic link between distinct developmental language disorders.2008] [Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons.2008] [Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS.2009] [Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.2009] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.2010] [Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.2010] [Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population.2010] [Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.2010] [Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.2010] [Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case.2010] [A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-relat...2011] [CNTNAP2 variants affect early language development in the general population.2011] [Reduced transcript expression of genes affected by inherited and de novo CNVs in autism.2011] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.2011] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Rare copy number variants are an important cause of epileptic encephalopathies.2011] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization.2012] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.2012] [Amino-Terminal Microdeletion within the CNTNAP2 Gene Associated with Variable Expressivity of Speech Delay.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [Defining the contribution of CNTNAP2 to autism susceptibility.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014]
7/1/2015
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

7/1/2016
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

7/1/2017
2S
icon
2S

Increased from 2S to 2S

Description

Syndromic because of apparent causative mutations in focal epilepsy and Pitt-Hopkins syndrome. Multiple lines of evidence point to CNTNAP2 in autism, including common SNP association to autism diagnosis (Arking et al., 2008; PMID: 18179894 and Anney et al, 2012; PMID: 22843504), a modest increase in the burden of rare variants identified by re-sequencing in individuals with autism (Bakkaloglu et al., 2008; PMID: 18179895), and common SNP association with quantitative language phenotype in individuals with autism (Alarcon et al., 2008; PMID: 18179893). Imaging evidence indicates that the language-associated SNP alters functional connectivity in the cerebral cortex (Vernes et al., 2008; PMID: 18987363; Scott-Van Zeeland et al., 2010; PMID: 21048216).

Krishnan Probability Score

Score 0.61403089293347

Ranking 134/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 3.8288260734217E-5

Ranking 13588/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.95084116029586

Ranking 18649/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 59

Ranking 27/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.28409542588975

Ranking 2965/20870 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.
CNVs associated with CNTNAP2(1 CNVs)
7q35-q36.1 4 Deletion-Duplication 7  /  5
Animal Models associated with CNTNAP2(26 Models)
CNTNAP2_1_KO_d4.1_Tg Genetic
CNTNAP2_2_KO_C2_Tg Genetic
CNTNAP2_3_KO_HM Genetic
CNTNAP2_4_KO_HM Genetic
CNTNAP2_5_KO_HM Genetic
CNTNAP2_5_KO_HM_AVP-1 RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_AVP-2 RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_AVPR-Ant_AVP RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_DREADD-OXTN RESCUE-Genetic
CNTNAP2_5_KO_HM_Fenobam RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_Flumazenil RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_Fluoxetine RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_MC4R-Ag RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_OXTR-Ant_AVP RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_OXTR-Ant_MC4R-Ag RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_OXTR-Ant_OXT RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_Oxytocin-1 RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_Oxytocin-2 RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_Oxytocin-3 RESCUE-Pharmaceutical
CNTNAP2_5_KO_HM_PV Genetic
CNTNAP2_5_KO_HM_PY Genetic
CNTNAP2_5_KO_HM_Risperidone RESCUE-Pharmaceutical
CNTNAP2_6_KO_HT Genetic
CNTNAP2_7_KO_HM_MIA_SD Multifactorial
CNTNAP2_8_KO_HM Genetic
CNTNAP2_9_KO_HM_MIA Multifactorial
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ADAM11 Disintegrin and metalloproteinase domain-containing protein 11 Mouse Protein Binding 11488 Q9R1V4
ADAM22 Disintegrin and metalloproteinase domain-containing protein 22 Mouse Protein Binding 11496 Q9R1V6
ADAM23 Disintegrin and metalloproteinase domain-containing protein 23 Mouse Protein Binding 23792 Q9R1V7
CASK calcium/calmodulin-dependent serine protein kinase (MAGUK family) Mouse Protein Binding 12361 O70589
CKMT1 Creatine kinase U-type, mitochondrial Mouse Protein Binding 12716 P30275
CNTN2 contactin 2 (axonal) Human Protein Binding 6900 Q02246
KCNA1 Potassium voltage-gated channel subfamily A member 1 Mouse Protein Binding 16485 P16388
KCNA2 potassium voltage-gated channel, shaker-related subfamily, member 2 Mouse Protein Binding 16490 P63141
KCNA3 Potassium voltage-gated channel subfamily D member 3 Mouse Protein Binding 56543 Q9Z0V1
KCNA4 potassium voltage-gated channel, shaker-related subfamily, member 4 Mouse Protein Binding 16492 Q61423
KCNA6 Potassium voltage-gated channel subfamily A member 6 Mouse Protein Binding 16494 Q61923
KCNAB2 Voltage-gated potassium channel subunit beta-2 Mouse Protein Binding 16498 P62482
LGI2 leucine-rich repeat LGI family, member 2 Mouse Protein Binding 246316 Q8K4Z0
LGI3 Leucine-rich repeat LGI family member 3 Mouse Protein Binding 213469 Q8K406
LGI4 Leucine-rich repeat LGI family member 4 Mouse Protein Binding 243914 Q8K1S1
Mpdz multiple PDZ domain protein Rat Protein Binding 29365 O55164
PDIA3 protein disulfide isomerase family A, member 3 Human Protein Binding 2923 P30101
STOX1 storkhead box 1 Human DNA Binding 219736 Q6ZVD7
TPI1 Triosephosphate isomerase Mouse Protein Binding 21991 P17751
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