Biallelic Variants in KMO Cause a Novel Form of Congenital NAD Deficiency

Congenital NAD deficiency disorder (CNDD) is a gene × environment disorder caused by disruptions of the kynurenine pathway. To date, CNDD has been associated with biallelic variants in three kynurenine pathway genes: KYNU, HAAO, and NADSYN1 . We identified two sisters with congenital anomalies overlapping with CNDD who have biallelic variants in a gene encoding a different kynurenine pathway enzyme, KMO . The surviving child also has elevated levels of metabolites upstream of KMO with low NAD ⁺ levels in plasma, suggesting that KMO deficiency is a novel CNDD. To explore the pathogenicity of KMO deficiency, we generated a global Kmo knockout mouse model ( Kmo ^-/- ) and utilized dietary interventions to better model human gene × environment interactions. Although Kmo ^-/- mice are viable and fertile on typical breeder chow, they exhibit elevated serum kynurenine and are functionally vitamin B3-dependent. Under conditions of limited maternal vitamin B3 intake, a greater proportion of Kmo ^-/- embryos develop congenital anomalies and have significantly lower NAD ⁺ levels than Kmo ^+/- littermates. Exploratory untargeted metabolomics performed in Kmo ^-/- embryos suggested that NAD ⁺ deficiency may perturb the pyrimidine, purine, and pentose phosphate pathways. These findings establish KMO deficiency as a new cause of CNDD and highlight a critical gene × environment interaction influencing NAD metabolism and congenital anomalies.