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

Biallelic variants in KMO, a kynurenine pathway enzyme, with accumulation of upstream metabolites and reduced NAD+; the Kmo knockout mouse model is functionally vitamin B3-dependent.

Congenital NAD deficiency disorder is a gene-environment disorder caused by disruption of the kynurenine pathway, so far associated with biallelic variants in three pathway genes, KYNU, HAAO and NADSYN1. The authors report two sisters with congenital anomalies overlapping this presentation who carry biallelic variants in a fourth pathway gene, KMO, the surviving child having elevated levels of metabolites upstream of KMO and low plasma NAD+. To explore pathogenicity they generated a global Kmo knockout mouse model and used dietary interventions to better model the human gene-environment interaction: these mice are viable and fertile on typical breeder chow but show elevated serum kynurenine and are functionally vitamin B3-dependent. Under limited maternal vitamin B3 intake, a greater proportion of knockout embryos develop congenital anomalies with significantly lower NAD+ levels than heterozygous littermates, and exploratory untargeted metabolomics suggests that NAD+ deficiency perturbs the pyrimidine, purine and pentose phosphate pathways.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A fourth gene in an already well-mapped pathway, with a mouse model that reproduces dependence on maternal vitamin B3 intake, is exactly the evidence structure that makes a gene interpretable in an exome already sequenced, without waiting for families to accumulate. Two reservations apply: a single human sibship, and a preprint not yet peer reviewed, which for now precludes reporting a KMO variant as causal outside a concordant biochemical context. Measuring kynurenine pathway metabolites together with plasma NAD+ is precisely the argument that will settle individual cases, and it should accompany any candidate variant.

Analysis by Dr Thibaut Benquey