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

Authors

Nathalie M Aceves-Ewing, Nanbing Li-Villarreal, Xiaohui Li, Seema R Lalani, Jill A Rosenfeld, Varduhi Petrosyan, Aleksandar Milosavljevic, Angelina Gaspero, Denise G Lanza, Audrey E Christiansen, Amrit Koirala, Abu Hena Mostafa Kamal, Nagireddy Putluri, Cristian Coarfa, Bao Tran, Philip L Lorenzi, Lin Tan, Charul Gijavanekar, Sarah H Elsea, Emily Lawrence, Hartmut Cuny, Sally L Dunwoodie, Pengfei Liu, Haonan Zhouyao, Tara L Rasmussen, Mary E Dickinson, Carlos A Bacino, Brendan Lee, Ronit Marom, Undiagnosed Diseases Network, BCM Center for Precision Medicine Models, Jason D Heaney, Chih-Wei Hsu, Lindsay C Burrage

Published in

medRxiv : the preprint server for health sciences. Aug 27, 2026. Epub Aug 27, 2026.

Abstract

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.

PMID:
42798303
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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