HAAO – Congenital Vertebral-Cardiac-Renal Anomalies Syndrome

Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from dietary L-tryptophan via the kynurenine pathway during embryogenesis, and 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) catalyzes a key step. Biallelic, inactivating variants in HAAO disrupt NAD synthesis, leading to multiple malformations of the heart, kidney, vertebrae, and limbs characteristic of congenital vertebral-cardiac-renal anomalies syndrome. Across two unrelated cohorts, a total of seven probands harboring autosomal recessive HAAO variants (five missense, two predicted loss-of-function) have been reported (PMID:33942433; PMID:28792876).

Inheritance of HAAO variants follows an autosomal recessive pattern, with no extended segregation data reported. Case series include five patients with homozygous or compound heterozygous missense changes (e.g., c.128G>A (p.Arg43Lys)) and two patients with predicted null alleles (nonsense or frameshift), all presenting with variable expressivity of multiorgan malformations. These genetic findings establish a recurrent variant spectrum and confirm that both missense and null alleles contribute to disease severity.

Functional assays demonstrate a loss-of-function mechanism: yeast genetic complementation assays reveal a marked reduction in NAD synthesis for both missense and frameshift HAAO variants (PMID:33942433). In parallel, in vitro enzyme activity assays and plasma metabolite quantification in affected individuals show severely diminished HAAO function and reduced circulating NAD levels (PMID:28792876).

Mouse models lacking Haao recapitulate the human malformation phenotype, affirming the pathogenic mechanism. Embryonic defects in Haao-null mice are prevented by maternal niacin supplementation, underscoring a potential prenatal therapeutic intervention (PMID:28792876).

No studies have disputed the role of HAAO in congenital NAD deficiency. The concordance of genetic, biochemical, and animal model data provides robust evidence linking HAAO loss-of-function to congenital vertebral-cardiac-renal anomalies syndrome. Key take-home: HAAO should be included in genetic testing panels for congenital multiorgan malformations, and gestational niacin supplementation may mitigate phenotypic severity.

References

• Human Mutation • 2021 • New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder. PMID:33942433
• The New England Journal of Medicine • 2017 • NAD Deficiency, Congenital Malformations, and Niacin Supplementation. PMID:28792876

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