KYNU – Congenital Vertebral-Cardiac-Renal Anomalies Syndrome

KYNU encodes kynureninase, an enzyme critical for de novo NAD synthesis via the tryptophan–kynurenine pathway. Biallelic inactivating variants in KYNU disrupt NAD production during embryogenesis, leading to multiple malformations of the vertebrae, heart, kidneys, and limbs, collectively referred to as congenital vertebral-cardiac-renal anomalies syndrome (VCRL; MONDO:0020831).

Clinical Validity

Using ClinGen criteria, the association between KYNU and VCRL is classified as Strong. This conclusion is based on biallelic, inactivating KYNU variants identified in four unrelated families ([PMID:33942433]) and three additional probands ([PMID:28792876]), with concordant loss-of-function demonstrated in functional assays and animal models.

Genetic Evidence

Inheritance is autosomal recessive. A total of seven probands from distinct families harbor biallelic KYNU variants, including frameshift and missense alleles that segregate with disease in homozygous or compound heterozygous states ([PMID:33942433]; [PMID:28792876]). One recurrent missense variant, c.1282C>T (p.Arg428Trp), has been reported in a patient with overlapping hand hyperphalangism and VCRL features ([PMID:31923704]). No additional affected relatives with segregation data have been reported.

Functional Evidence

KYNU variants cause marked NAD depletion in yeast complementation assays, confirming loss-of-function ([PMID:33942433]). In Kynu-null mice engineered via CRISPR–Cas9, embryos replicate human vertebral, cardiac, and renal malformations; prenatal niacin supplementation rescues these defects by restoring NAD levels ([PMID:28792876]). These data define haploinsufficiency of KYNU as the disease mechanism.

Conflicting Evidence

No studies to date have refuted the role of KYNU in VCRL or proposed alternative aetiologies for these congenital anomalies.

Integrated Conclusion

Genetic and experimental data robustly support a pathogenic role for biallelic KYNU loss-of-function variants in congenital vertebral-cardiac-renal anomalies syndrome. Functional assays and rescue studies provide a clear mechanistic link via NAD deficiency.

Key Take-home: KYNU sequencing should be included in diagnostic workups for neonates with vertebral, cardiac, renal, or limb malformations, and prenatal niacin supplementation represents a potential therapeutic strategy.

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
• Bone • 2020 • Biallelic variants in KYNU cause a multisystemic syndrome with hand hyperphalangism. PMID:31923704

Evidence Based Scoring (AI generated)