Gene Validity Curation

CNTNAP2 - autism (disease)

Gene: CNTNAP2 (HGNC:13830)
Classification - 09/18/2019
Disease: autism (disease) (MONDO_0005260)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: Three seminal papers indicated an association of CNTNAP2 with autism susceptibility (Arking et al 2008 PMID: 18179894; Alarcon et al. 2008 PMID: 8179893; Bakkaloglu et al. 2008 PMID: 18179895). Arking and Alarcon implicated two polymorphisms/ SNPs, rs7794745 and rs2710102, respectively. Since these seminal papers, contradictory evidence has in the form of several case control studies have shown no association of CNTNAP2 with autism susceptibility. Furthermore, a paper by Murdoch et al., 2015 (PMID:25621974) is a follow up from the Bakkaloglu et al., 2008, and reuses the original data and performs updated and more reliable comparisons, as well as uses updated SIFT and PolyPhen-2 data and found no evidence of an association, and thus they disputed their prior claim. Furthermore, the SNPs rs7794745 and rs2710102 have a maximum MAF of 0.7623 and 0.6873, respectively, in the African population and are observed in over 1000 homozygotes, indicating a benign allele. Lastly, Alarcon asserted that while rs2710102 may have had some statistical enrichment it was likely indicative of linkage disequilibrium with another functional variant. No experimental evidence was applicable to the curation as it was not specific to the given gene disease relationship, and could overlap with other disease entities asserted to be associated with CNTNAP2 (see below). CNTNAP2 is associated with autosomal recessive cortical dysplasia-focal epilepsy syndrome, which is also referred to as Pitt-Hopkins like syndrome 1 (MIM# 610042 for both phenotypes) and well as autosomal dominant Autism susceptibility (MIM# 612100). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in the assertions, molecular mechanism, phenotypic expressivity, and inheritance pattern between the two disease entities asserted. Therefore, the curation of CNTNAP2 with autosomal recessive cortical dysplasia-focal epilepsy syndrome constitutes a separate curation, and was performed by the ClinGen Epilepsy Gene Curation Expert Panel. Of note, the autosomal dominant, carrier parents of individuals with autosomal recessive autosomal recessive cortical dysplasia-focal epilepsy syndrome, in general, were not noted to have phenotypes, consistent with separate disease mechanisms between autism susceptibility and autosomal recessive cortical dysplasia-focal epilepsy syndrome. In summary, there is convincing evidence refuting the relationship of CNTNAP2 and autosomal dominant autism, which significantly outweighs the evidence supporting the relationship. This classification was approved by the ClinGen Intellectual disability and Autism Working Group on September 19, 2019.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 3
0
0
Toma C et al. 2013 Apr (PMID:23277129); Poot M et al. 2014 Aug (PMID:25337070);
Aggregate Variant Analysis 0-6 3
0
Bakkaloglu B et al. 2008 Jan (PMID:18179895); Murdoch JD et al. 2015 Jan (PMID:25621974); Li J et al. 2017 Sep (PMID:28831199);
Total Genetic Evidence Points (Maximum 12) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 0 0 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
No Classification
11/19/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Refuted
11/19/2019
REASON(S) FOR CHANGE
Three seminal papers indicated an association of CNTNAP2 with autism susceptibility (Arking et al 2008 PMID: 18179894; Alarcon et al. 2008 PMID: 8179893; Bakkaloglu et al. 2008 PMID: 18179895). Arking and Alarcon implicated two polymorphisms/ SNPs, rs7794745 and rs2710102, respectively. Since these seminal papers, contradictory evidence has in the form of several case control studies have shown no association of CNTNAP2 with autism susceptibility. Furthermore, a paper by Murdoch et al., 2015 (PMID:25621974) is a follow up from the Bakkaloglu et al., 2008, and reuses the original data and performs updated and more reliable comparisons, as well as uses updated SIFT and PolyPhen-2 data and found no evidence of an association, and thus they disputed their prior claim. Furthermore, the SNPs rs7794745 and rs2710102 have a maximum MAF of 0.7623 and 0.6873, respectively, in the African population and are observed in over 1000 homozygotes, indicating a benign allele. Lastly, Alarcon asserted that while rs2710102 may have had some statistical enrichment it was likely indicative of linkage disequilibrium with another functional variant. Thus, there is overwhelming evidence to refute the claim of a relationship of CNTNAP2 with Autism.
EXPERT CURATION (DATE)
Refuted
09/18/2019
EVIDENCE SUMMARY
Three seminal papers indicated an association of CNTNAP2 with autism susceptibility (Arking et al 2008 PMID: 18179894; Alarcon et al. 2008 PMID: 8179893; Bakkaloglu et al. 2008 PMID: 18179895). Arking and Alarcon implicated two polymorphisms/ SNPs, rs7794745 and rs2710102, respectively. Since these seminal papers, contradictory evidence has in the form of several case control studies have shown no association of CNTNAP2 with autism susceptibility. Furthermore, a paper by Murdoch et al., 2015 (PMID:25621974) is a follow up from the Bakkaloglu et al., 2008, and reuses the original data and performs updated and more reliable comparisons, as well as uses updated SIFT and PolyPhen-2 data and found no evidence of an association, and thus they disputed their prior claim. Furthermore, the SNPs rs7794745 and rs2710102 have a maximum MAF of 0.7623 and 0.6873, respectively, in the African population and are observed in over 1000 homozygotes, indicating a benign allele. Lastly, Alarcon asserted that while rs2710102 may have had some statistical enrichment it was likely indicative of linkage disequilibrium with another functional variant. No experimental evidence was applicable to the curation as it was not specific to the given gene disease relationship, and could overlap with other disease entities asserted to be associated with CNTNAP2 (see below). CNTNAP2 is associated with autosomal recessive cortical dysplasia-focal epilepsy syndrome, which is also referred to as Pitt-Hopkins like syndrome 1 (MIM# 610042 for both phenotypes) and well as autosomal dominant Autism susceptibility (MIM# 612100). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in the assertions, molecular mechanism, phenotypic expressivity, and inheritance pattern between the two disease entities asserted. Therefore, the curation of CNTNAP2 with autosomal recessive cortical dysplasia-focal epilepsy syndrome constitutes a separate curation, and was performed by the ClinGen Epilepsy Gene Curation Expert Panel. Of note, the autosomal dominant, carrier parents of individuals with autosomal recessive autosomal recessive cortical dysplasia-focal epilepsy syndrome, in general, were not noted to have phenotypes, consistent with separate disease mechanisms between autism susceptibility and autosomal recessive cortical dysplasia-focal epilepsy syndrome. In summary, there is convincing evidence refuting the relationship of CNTNAP2 and autosomal dominant autism, which significantly outweighs the evidence supporting the relationship. This classification was approved by the ClinGen Intellectual disability and Autism Working Group on September 19, 2019.