NADSYN1 – Congenital NAD Deficiency Disorder

Nicotinamide adenine dinucleotide (NAD) is essential for multiple redox and non-redox reactions. Biallelic variants in NADSYN1 cause autosomal recessive congenital NAD deficiency disorder (Vertebral-Cardiac-Renal-Limb syndrome) (PMID:33942433).

Genetic evidence includes seven pediatric probands reported by Szot et al. and Kortbawi et al. and a 30-year-old adult patient with characteristic skeletal, cardiac, and craniofacial anomalies (PMID:36649848). All affected individuals harbor homozygous or compound heterozygous NADSYN1 variants; unaffected parents are carriers, confirming recessive inheritance.

The variant spectrum comprises primarily missense changes and a few loss-of-function alleles. A recurrent missense variant c.1717G>A (p.Ala573Thr) was observed in four patients (PMID:36649848), and a canonical splice variant c.799-2A>G was identified in congenital vertebral malformation cohorts (PMID:34681008). Segregation has been demonstrated in multiple families with biallelic inheritance.

Functional studies in yeast complementation assays demonstrate that missense and frameshift variants abolish NAD synthetase activity, causing severe NAD depletion (PMID:33942433). In vitro expression in COS-7 cells shows markedly reduced protein levels and enzymatic function for both truncating and missense variants (PMID:34681008).

Clinically, affected individuals present with vertebral segmentation defects, abnormal rib morphology, limb anomalies, bilateral ptosis (HP:0001488), cleft palate (HP:0000175), and cardiac malformations including bicuspid aortic valve (PMID:36649848). Secondary NAD measurements confirm deficiency and partial restoration following nicotinamide supplementation.

Integration of genetic and experimental data provides strong support for the gene–disease association. Biallelic NADSYN1 loss-of-function underlies congenital NAD deficiency disorder. Key take-home: NADSYN1 sequencing enables definitive diagnosis, informs carrier screening, and guides NAD precursor therapeutic strategies.

References

• Human Mutation | 2021 | New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder PMID:33942433
• Genes | 2021 | Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations PMID:34681008
• European Journal of Medical Genetics | 2023 | Adult patient diagnosed with NADSYN1 associated congenital NAD deficiency and analysis of NAD levels PMID:36649848

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