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Clinical cardiopulmonary evaluations did not reveal abnormalities, but the blood remained dark after exposure to air. Erythrocytic methemoglobin concentrations were high (~40% of hemoglobin) and cytochrome b5 reductase (CYB5R) activities in erythrocytes were low (\u226415% of control). One cat remained intolerant of exertion, and the other cat developed anemia and died due to an unidentified comorbidity. Whole-genome sequencing revealed a homozygous c.625G&amp;gt;A missense variant (B4:137967506) and a c.232-1G&amp;gt;C splice acceptor variant (B4:137970815) in CYB5R3, respectively, which were absent in 193 unaffected additional cats. The p.Gly209Ser missense variant likely disrupts a nicotinamide adenine dinucleotide (NADH)-binding domain, while the splicing error occurs at the acceptor site for exon 4, which likely affects downstream translation of the protein. The 2 novel CYB5R3 variants were associated with methemoglobinemia using clinical, biochemical, genomics, and in silico protein studies. The variant prevalence is unknown in the cat population.<\/jats:p>","DOI":"10.1111\/jvim.15637","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T03:54:44Z","timestamp":1571975684000},"page":"2725-2731","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats"],"prefix":"10.1093","volume":"33","author":[{"name":"the 99 Lives Cat Genome Consortium","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0270-4728","authenticated-orcid":false,"given":"Jared A.","family":"Jaffey","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Midwestern University Department of Veterinary Medicine and Surgery, , Glendale, Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N. Scott","family":"Reading","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Pathology, ARUP Laboratories , Salt Lake City, Utah"},{"name":"Division of Hematology , Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah"},{"name":"University of Utah School of Medicine Department of Pathology, , Salt Lake City, Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urs","family":"Giger","sequence":"additional","affiliation":[{"name":"Section of Medical Genetics (PennGen), School of Veterinary Medicine, University of Pennsylvania , Philadelphia, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osheiza","family":"Abdulmalik","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben 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