Homozygous Variant in NADSYN1 Causes Multiple Congenital Vertebral Malformation, With Neurodevelopmental Disorder

Congenital NAD deficiency (CNDD) is a rare autosomal recessive disorder characterized by multiple congenital anomalies, frequently affecting the spine, kidneys, heart and nervous system. NADSYN1 is one of the genes of the NAD pathway that is mutated in CNDD. Here, we report a 5-year-old boy from a consanguineous family presenting with multiple vertebral segmentation defects, developmental delay and intellectual and speech impairment. To identify the disease-causing variant, whole-exome sequencing (WES) coupled with Sanger sequencing was performed. WES identified a biallelic missense variant c.193C>T (p.His65Tyr) in the NADSYN1 gene affecting a highly conserved amino acid within the glutaminase domain. This case expands the clinical and mutational spectrum of NADSYN1 related CNDD, highlighting a predominantly skeletal phenotype with neurodevelopmental involvement and emphasizing the importance of NAD biosynthesis in early development.