Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CHD7 : CHARGE syndrome

HGNC:20626 | MONDO_0008965
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
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
Vissers LE et al. 2004 Sep (PMID:15300250); Lee B et al. 2016 Feb 1 (PMID:26551301); Sohn YB et al. 2016 Mar (PMID:26538304);
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 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 1
Aramaki M et al. 2007 Jan (PMID:17149726); Bajpai R et al. 2010 Feb 18 (PMID:20130577);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1
Bajpai R et al. 2010 Feb 18 (PMID:20130577);
Models Non-human model organism 2 0 - 4 4 4 4
Zentner GE et al. 2010 Mar (PMID:20186815); Hurd EA et al. 2007 Feb (PMID:17334657);
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) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The CHD7 gene was first associated with autosomal dominant CHARGE syndrome in humans as early as 2004 (Vissers et al.). Association is seen in many probands (over 200 pathogenic variants have been submitted to ClinVar), but for the purpose of this curation, evidence was maxed by scoring 6 probands in 3 publications (PMID: 15300250, 26551301, 26538304). Of note, CHD7 has also been associated with Kallmann syndrome, which is characterized by hypogonadotropic hypogonadism and anosmia which are both features of CHARGE syndrome (PMID: 23533228). Patients with variants in CHD7 have also presented with isolated hypogonadotropic hypogonadism (IHH; PMID: 30098700). Furthermore, additional features of CHARGE syndrome have been reported in some patients with Kallmann syndrome and hypogonadotrophic hypogonadism who harbor pathogenic CHD7 variants (PMID: 23533228, 25077900, 22399515, 30098700). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in CHD7. Therefore, the three conditions have been lumped into the disease entity of CHARGE syndrome. All scored variants arose de novo. Pathogenic variants include predicted loss-of-function (nonsense, frameshift, canonical splice sites), missense and full and partial gene deletions suggesting the mechanism of pathogenicity is loss of function. The gene-disease association is supported by multiple animal models, expression studies, and in vitro functional assays (PMID: 20130577, 20186815, 17334657). Therefore, this association was classified as Definitive by the ClinGen Hearing Loss Expert Panel on 6/26/2018. Additionally, neurodevelopmental issues have been observed in some individuals with CHARGE syndrome and it has been claimed that these issues may be attributed to hearing/vision impairments though this correlation has not been found to be significant by one study (PMID: 12828403). Though developmental delay is considered a "minor" feature of CHARGE syndrome (PMID: 20301296), CHD7 is still tested as part of a number of clinical genetic testing panels marketed for neurodevelopmental disorders. As such, on 8/15/2018 the ClinGen ID/Autism Gene Curation Expert Panel evaluated the evidence originally assessed and classified as Definitive by the ClinGen Hearing Loss Expert Panel. While the ID/Autism Expert Panel agreed that CHD7 is definitively associated with CHARGE syndrome, they note that there is a large degree of variation in the presence of intellectual disability in CHD7 patients and no animal model of CHD7-associated CHARGE syndrome has provided evidence for the ID phenotype. In summary, although the spectrum of phenotypic features that are primary attributes of CHARGE syndrome are still being defined, the ClinGen Hearing Loss and ID/Autism Expert Panels have classified the overall association with CHARGE syndrome as Definitive as of 8/15/2018.