CYB5A was first reported in relation to autosomal recessive methemoglobinemia 4 by Giordano et al. in 1994 (PMID: 8168836) in a family that had previously been reported in 1986 (Hegesh et al., PMID: 3951505). Methemoglobinemia 4, also referred to as methemoglobinemia and ambiguous genitalia (MIM#250790) or pure isolated 17,20-lyase deficiency, is characterized by mildly elevated serum methemoglobin, cyanosis, and 46,XY disorder of sexual differentiation (DSD). The cytochrome b5 protein encoded by CYB5A interacts with cytochrome P450 17A1 and stimulates 17,20-lyase activity, which is required for the synthesis of androgen hormones. Biallelic loss of CYB5A expression or disruption of this interaction leads to 46,XY DSD. To date, only one 46,XX proband with biallelic variants in CYB5A has been reported. This individual showed no evidence of DSD or other symptoms beyond elevated serum methemoglobin and cyanosis (PMID: 32051920).
Six variants (missense, in-frame indel, nonsense, canonical splice acceptor site) that have been reported in five probands in five publications (PMIDs: 8168836, 20080843, 22170710, 32051920, 33626548) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, in vitro functional assays of wild-type function, and demonstrated protein-protein interactions with P450 17A1 (PMIDs: 20430864, 25613900, 26974035, 33753170, 34610701, 36441026).
In summary, there is definitive evidence supporting the relationship between CYB5A and autosomal recessive methemoglobinemia 4. This association been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on November 8, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.