CRH

Inheritance Pattern: AD

Disease ID:MONDO:0020300

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0002612

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

The CRH gene encodes the corticotropin releasing hormone, a hormone and neuropeptide that plays a role in stress response through the hypothalamus-pituitary-adrenal axis. CRH was first reported in relation to autosomal dominant epilepsy in 2005 (Combi et al, PMID: 16222669). Although the phenotype of the asserted gene-disease association was autosomal dominant nocturnal frontal lobe epilepsy, the curation was performed for the higher-level term, epilepsy, because the available evidence does not support an association between the CRH gene and epilepsy of any kind. All the published evidence comes from a series of studies by a single research group. CRH was initially selected as a candidate gene from within a linkage region on chromosome 8q (Combi et al 2005, PMID: 16182932). During this curation, the expert panel raised concerns about the methodology of that study, including the treatment of unaffected individuals as affected for the linkage analysis, the use of an autosomal dominant model in a pedigree with only one affected generation, and a LOD score that was statistically non-significant. All follow-up studies listed in this curation sequenced only one gene, CRH, and did not use genome-wide testing methods. Across several reports, two non-coding single nucleotide variants in the gene’s promoter region and one missense variant were identified in six families. In all six of these families, variant segregation failed to support an association of these variants with the phenotype (see curation for details). Each of the variants identified is present in population databases. Therefore, none of the published genetic-level evidence was given a score in this curation. Although experimental evidence was provided in two of the studies (Combi et al 2005, PMID: 16222669; Sansoni et al 2013, PMID: 23593457), the assays reported have no known connection to epilepsy as a phenotype, and therefore were not scored in this curation. The consensus opinion of the gene curation expert panel was that the identified variants appear to be population variants and based on current knowledge all published assertions of this gene-disease association can be refuted. In summary, the evidence supporting the relationship between CRH and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. New evidence would be needed to support this claim. This classification was approved by the ClinGen Epilepsy Expert Panel on the meeting date 9/21/21 (SOP Version 8).