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Gene: CYB5R3

Green List (high evidence)

CYB5R3 defect results in two types of congenital methemoglobinemia depending on the deficiency in one or both the isozymes:

1. Type I
- Enzyme deficiency restricted only in erythrocytes and usually present with no clinical manifestations other than cyanosis
- Typically associated with missense mutations that result in amino acid substitution responsible for enzymatically active but unstable proteins correlating with the benign clinical course of the disease

2. Type II
- Severe form of disease, less common than Type I
- Progressive and leads to shortened lifespan (OMIM)
- Presents with neurological damage manifested by severe psychomotor retardation, hypotonia, microcephaly and neuroimaging abnormalities.
- Enzyme deficiency in the red cells along with other blood elements, brain, liver, and fibroblasts resulting in disturbances of all metabolic processes that involve CYB5R3 eg cholesterol biosynthesis and fatty acids desaturation and elongation important for normal brain development.
- Typically associated with PTCs or deletions located in consensus FAD or NADH-binding sites of enzyme causing loss of protein expression or enzymatically inactivate proteins leading to severe neurological impairment

Green for Methemoglobinemia, type II (MIM#250800), type I not included in review as seems mild

Created: 10 Jan 2025, 5:40 a.m. | Last Modified: 10 Jan 2025, 5:40 a.m.

Panel Version: 1.992

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Methemoglobinemia, type II (MIM# 250800)

Publications

• 31898843
• 38303731

Variants in this GENE are reported as part of current diagnostic practice