NADSYN1 encodes NAD synthetase 1, which catalyzes the final ATP-dependent step of nicotinamide adenine dinucleotide (NAD) de novo synthesis, converting deamido-NAD to NAD using L-glutamine as a nitrogen source 1. This enzyme is essential for cellular metabolism and organ embryogenesis, operating primarily in the cytoplasm and cytosol. Biallelic loss-of-function variants in NADSYN1 cause congenital NAD deficiency disorder (CNDD), characterized by vertebral, cardiac, renal, and limb defects (VCRL syndrome) 23. Clinical severity ranges from severe prenatal lethality to mild presentations, even with identical mutations in siblings, indicating significant phenotypic heterogeneity 2. Functional studies demonstrate that pathogenic variants reduce protein levels or disrupt enzymatic activity 3. Affected pregnancies can be prevented through maternal supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) in homozygous mothers, while any B3 vitamer suffices for heterozygous mothers 1. A consistent NAD metabolome signature aids clinical diagnosis, and decreased plasmatic NAD levels should trigger screening for NADSYN1 variants even in patients with isolated organ involvement rather than the complete VCRL spectrum 21. Genetic variants in NADSYN1 are also associated with vitamin D metabolism and influenced Parkinson's disease clinical features in population studies 45, though these associations require further clarification.