Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CHD8 : autism spectrum disorder

HGNC:20153 | MONDO_0005258
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
14
12
O'Roak BJ et al. 2012 Apr 4 (PMID:22495309); Bernier R et al. 2014 Jul 17 (PMID:24998929); Merner N et al. 2016 May (PMID:26789910); Wang T et al. 2016 Nov 8 (PMID:27824329);
Proband with predicted or proven null variant 1.5 0-2 10 1.5 1.5
Bernier R et al. 2014 Jul 17 (PMID:24998929);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max 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 3.5 3.5
Bernier R et al. 2014 Jul 17 (PMID:24998929); Nishiyama M et al. 2012 Jan (PMID:22083958); Katayama Y et al. 2016 Sep 29 (PMID:27602517);
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) 3.5

 


 

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 12 3.5 15.5 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)
Definitive
08/27/2018
EXPERT CURATION (DATE)
Definitive
08/27/2018
EVIDENCE SUMMARY
The CHD8 gene has been associated with autosomal dominant autism spectrum disorder using the ClinGen Clinical Validity Framework as of 7/11/2018​. At least 8 frameshift and nonsense variants have been reported in humans. CHD8​ was first associated with this disease in humans as early as 2012 (O'Roak et al.​). Association is seen in at least 8 probands in 4​ publications (22495309, 24998929, 26789910, 27824329​). Of note, one individual inherited a CHD8 variant from a heterozygous mother who has some autistic features but has not been clinically diagnosed. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a zebrafish model and a mouse model. In summary, CHD8​ is definitively associated with autosomal dominant autism spectrum disorder. This classification was approved by the ClinGen Autism and Intellectual Disability​ Working Group on 7/16/2018​.