Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations

Area of Science:

• Genetics
• Developmental Biology
• Biochemistry

Background:

• Nicotinamide adenine dinucleotide (NAD) is crucial for cellular metabolism and organ development.
• Genetic defects in the de novo NAD synthesis pathway are linked to congenital birth defects.
• The NADSYN1 gene encodes the key enzyme in NAD synthesis and its mutations cause VCRL syndrome.

Purpose of the Study:

• To investigate the role of NADSYN1 gene variants in patients with congenital vertebral malformations (CVMs).
• To identify novel genetic causes of CVMs and related congenital organ defects.

Main Methods:

• Exome sequencing of patients with CVMs.
• Analysis of genetic variants in the NADSYN1 gene.
• In vitro functional assays (COS-7 cells) to assess protein levels and enzymatic activity of identified variants.

Main Results:

• Eight NADSYN1 variants (2 truncating, 6 missense) were identified in nine unrelated patients with CVMs.
• Patients presented with multiple organ defects (heart, kidney, limbs, liver) and intraspinal deformities.
• In vitro assays confirmed reduced protein levels or impaired enzymatic activity for the identified variants.

Conclusions:

• Functional variants in NADSYN1 contribute to the genetic etiology of CVMs.
• These findings provide further evidence for NADSYN1 variants causing congenital NAD Deficiency Disorder.
• Disruptions in NAD synthesis are implicated in complex congenital organ malformations.