CHD7

Inheritance Pattern: AD

Disease ID:MONDO:0008965

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008965

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011338

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008965

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008965

Submitter: ClinGen

The CHD7 gene was first associated with autosomal dominant CHARGE syndrome in 2004 (PMID: 15300250). Since that initial report, the association has been replicated extensively, with hundreds of pathogenic variants reported across the gene. For the purpose of this curation, genetic evidence score was maxed by scoring 6 probands from 3 publications (PMID: 15300250, 26551301, 26538304). Of note, the phenotypic spectrum associated with heterozygous pathogenic variants in CHD7 extends beyond individuals who meet the clinical diagnostic criteria for CHARGE syndrome. CHD7 has also been associated with Kallmann syndrome, 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). Congenital heart disease was reported in 74% of individuals with pathogenic CHD7 variants, with a higher prevalence in those with truncating variants or deletions (80%) compared to those with missense or splice-site variants (80% versus 58% respectively) (PMID:23677905). 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 nonsense, frameshift, canonical splice sites, missense and whole or partial gene deletions. The established disease mechanism is loss of function. The gene-disease relationship is further 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 manifestations 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). Although developmental delay is considered a "minor" feature of CHARGE syndrome (PMID: 20301296), CHD7 is included on many clinical genetic testing panels 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 variability 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. On 6/3/2026, the SCID/CID Gene Curation Expert Panel evaluated the evidence curated by the ClinGen Hearing Loss Gene Curation Expert Panel and also agreed that CHD7 is Definitively associated with CHARGE syndrome. However, pathogenic heterozygous loss of function variants in CHD7 are also known to result in immune deficiency in some individuals (PMID: 26563674) due to abnormal development of the thymus (PMIDs: 29353058, 32922396, and 40528267). The thymus is not affected in all individuals, and the degree of thymic loss varies in a manner that is not genotype-specific. The immune phenotype predominantly consists of T cell lymphopenia that is detectable at birth with normal B and NK cell counts (PMIDs: 17684005, 18976358, 26563674). For individuals whose defect results in complete athymia, the T cell lymphopenia is profound and causes severe T and functional B cell deficiency that is corrected by allogenic thymus tissue implantation (PMIDs: 17931565, 33987750, 34362576). Otherwise, individuals with a hypoplastic rather than aplastic thymus have low T cell counts but exhibit normal T cell responses to mitogens and antigens as well as normal B cell antibody production. 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.

Inheritance Pattern: AD

Disease ID:MONDO:0012880

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008965

Submitter: Broad Center for Mendelian Genomics

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet