| Gene/Disease Pair: | CHD8 : autism spectrum disorder |
| HGNC:20153 | MONDO_0005258 | |
| Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
| Expert Panel: | Autism and Intellectual Disability EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 5 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Total | Counted | ||||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
14
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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);
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| 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);
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| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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| 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 |
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| 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 | ||||||||||
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Case-Control Data
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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 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | |||||||
| Default | Range | Max | Total | Counted | ||||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
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| Protein Interaction | 0.5 | 0 - 2 | ||||||||||
| Expression | 0.5 | 0 - 2 | ||||||||||
| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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| 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);
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| Cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| 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 |
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| 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)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
08/27/2018
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| EXPERT CURATION (DATE) |
Definitive
08/27/2018
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| 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.
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